53 results on '"Hsiang-Chun Chang"'
Search Results
2. Data from RNA Helicase DDX5 Is a p53-Independent Target of ARF That Participates in Ribosome Biogenesis
- Author
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Jason D. Weber, Loren S. Michel, R. Reid Townsend, Jianbo Wang, Raleigh D. Kladney, Anthony J. Apicelli, Crystal L. Winkeler, Hsiang-Chun Chang, and Anthony J. Saporita
- Abstract
The p19ARF tumor suppressor limits ribosome biogenesis and responds to hyperproliferative signals to activate the p53 checkpoint response. Although its activation of p53 has been well characterized, the role of ARF in restraining nucleolar ribosome production is poorly understood. Here we report the use of a mass spectroscopic analysis to identify protein changes within the nucleoli of Arf-deficient mouse cells. Through this approach, we discovered that ARF limited the nucleolar localization of the RNA helicase DDX5, which promotes the synthesis and maturation of rRNA, ultimately increasing ribosome output and proliferation. ARF inhibited the interaction between DDX5 and nucleophosmin (NPM), preventing association of DDX5 with the rDNA promoter and nuclear pre-ribosomes. In addition, Arf-deficient cells transformed by oncogenic RasV12 were addicted to DDX5, because reduction of DDX5 was sufficient to impair RasV12-driven colony formation in soft agar and tumor growth in mice. Taken together, our findings indicate that DDX5 is a key p53-independent target of the ARF tumor suppressor and is a novel non-oncogene participant in ribosome biogenesis. Cancer Res; 71(21); 6708–17. ©2011 AACR.
- Published
- 2023
3. Supplementary Methods from RNA Helicase DDX5 Is a p53-Independent Target of ARF That Participates in Ribosome Biogenesis
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Jason D. Weber, Loren S. Michel, R. Reid Townsend, Jianbo Wang, Raleigh D. Kladney, Anthony J. Apicelli, Crystal L. Winkeler, Hsiang-Chun Chang, and Anthony J. Saporita
- Abstract
PDF file - 102K
- Published
- 2023
4. Supplementary Figure 2 from RNA Helicase DDX5 Is a p53-Independent Target of ARF That Participates in Ribosome Biogenesis
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Jason D. Weber, Loren S. Michel, R. Reid Townsend, Jianbo Wang, Raleigh D. Kladney, Anthony J. Apicelli, Crystal L. Winkeler, Hsiang-Chun Chang, and Anthony J. Saporita
- Abstract
PDF file - 1.4MB
- Published
- 2023
5. SIRT2 inhibition protects against cardiac hypertrophy and heart failure
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Xiaoyan Yang, Hsiang-Chun Chang, Yuki Tatekoshi, Maryam Balibegloo, Rongxue Wu, Chunlei Chen, Tatsuya Sato, Jason Shapiro, and Hossein Ardehali
- Subjects
Article - Abstract
Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of heart failure (HF) and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion ofSirt2(Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specificSirt2deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion ofNrf2in the hearts ofSirt2-/-mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitors reduces cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in the progression of HF and cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of this disorder.
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- 2023
6. Iron Drives Anabolic Metabolism Through Active Histone Demethylation and mTORC1
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Jason Shapiro, Hsiang-Chun Chang, Zibo Zhao, Zohra Waxali, Bong Jin Hong, Haimei Chen, Justin Geier, Elizabeth Bartom, Adam De Jesus, Farnaz Keyhani-Nejad, Tatsuya Sato, Lucia Ramos-Alonso, Antonia Romero, María Teresa Martínez-Pastor, Shang-Chuan Jiang, Shiv K. Sah-Teli, Liming Li, David Bentrem, Gary Lopaschuk, Issam BEN-SAHRA, Thomas O'Halloran, Ali Shilatifard, Sergi Puig, Joy Bergelson, Peppi Koivunen, and Hossein Ardehali
- Abstract
All living cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here, we report a universal eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of genes encoding high-affinity leucine transporters and RAPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency (ID) supersedes other nutrient inputs into mTORC1. This process occurs in vivo, and is not an indirect effect by canonical iron-utilizing pathways. Elevated expression of KDM3B targets is associated with reduced survival in a subset of human cancers and ID represses mTORC1 in patient-derived tumor cells and sensitizes cancer cells to chemotherapy. These data demonstrate a novel mechanism of eukaryotic iron sensing through dynamic chromatin remodeling and repression of mTORC1 mediated anabolism. Due to ancestral eukaryotes sharing homologues of KDMs and mTORC1 core components, this pathway likely predated the emergence of the other kingdom-specific nutrient sensors for mTORC1.
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- 2022
7. ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice
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Hidemichi Kouzu, Yuki Tatekoshi, Hsiang-Chun Chang, Jason S. Shapiro, Warren A. McGee, Adam De Jesus, Issam Ben-Sahra, Zoltan Arany, Jonathan Leor, Chunlei Chen, Perry J. Blackshear, and Hossein Ardehali
- Subjects
Pregnancy Complications, Cardiovascular ,Nuclear Proteins ,General Medicine ,Mechanistic Target of Rapamycin Complex 1 ,Mice ,Peroxidases ,Tristetraprolin ,Pregnancy ,Peripartum Period ,Animals ,Female ,Myocytes, Cardiac ,RNA, Messenger ,Tumor Suppressor Protein p53 ,Cardiomyopathies ,Transcription Factors - Abstract
Pregnancy is associated with substantial physiological changes of the heart, and disruptions in these processes can lead to peripartum cardiomyopathy (PPCM). The molecular processes that cause physiological and pathological changes in the heart during pregnancy are not well characterized. Here, we show that mTORc1 was activated in pregnancy to facilitate cardiac enlargement that was reversed after delivery in mice. mTORc1 activation in pregnancy was negatively regulated by the mRNA-destabilizing protein ZFP36L2 through its degradation of Mdm2 mRNA and P53 stabilization, leading to increased SESN2 and REDD1 expression. This pathway impeded uncontrolled cardiomyocyte hypertrophy during pregnancy, and mice with cardiac-specific Zfp36l2 deletion developed rapid cardiac dysfunction after delivery, while prenatal treatment of these mice with rapamycin improved postpartum cardiac function. Collectively, these data provide what we believe to be a novel pathway for the regulation of mTORc1 through mRNA stabilization of a P53 ubiquitin ligase. This pathway was critical for normal cardiac growth during pregnancy, and its reduction led to PPCM-like adverse remodeling in mice.
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- 2022
8. Optimized protocol for quantification of mitochondrial non-heme and heme iron content in mouse tissues and cultured cells
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Tatsuya Sato, Hsiang-Chun Chang, Konrad T. Sawicki, and Hossein Ardehali
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General Immunology and Microbiology ,General Neuroscience ,General Biochemistry, Genetics and Molecular Biology - Published
- 2023
9. Aging is associated with increased brain iron through cortex-derived hepcidin expression
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Tatsuya Sato, Jason Solomon Shapiro, Hsiang-Chun Chang, Richard A Miller, and Hossein Ardehali
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Aging ,Mouse ,General Immunology and Microbiology ,QH301-705.5 ,Science ,Iron ,General Neuroscience ,Short Report ,Brain ,Gene Expression ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,Mice, Inbred C57BL ,Mice ,Hepcidins ,Medicine ,oxidative stress ,Animals ,Female ,Biology (General) - Abstract
Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrated that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain cortex exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, ferroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.
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- 2022
10. Author response: Aging is associated with increased brain iron through cortex-derived hepcidin expression
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Tatsuya Sato, Jason Solomon Shapiro, Hsiang-Chun Chang, Richard A Miller, and Hossein Ardehali
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- 2021
11. Re-Attention Is All You Need: Memory-Efficient Scene Text Detection via Re-Attention on Uncertain Regions
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Hsiang-Chun Chang, Hung-Jen Chen, Yu-Chia Shen, Hong-Han Shuai, and Wen-Huang Cheng
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- 2021
12. Aging is associated with increased brain iron through brain-derived hepcidin expression
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Tatsuya Sato, Hsiang-Chun Chang, Hossein Ardehali, Richard A. Miller, and Jason S. Shapiro
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Muscle tissue ,medicine.medical_specialty ,Messenger RNA ,biology ,Chemistry ,Oxidative phosphorylation ,medicine.disease_cause ,Cytosol ,medicine.anatomical_structure ,Endocrinology ,Ubiquitin ,Hepcidin ,Internal medicine ,biology.protein ,medicine ,Cellular compartment ,Oxidative stress - Abstract
Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrate that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, feroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.
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- 2021
13. Development of dipyridine‐based coordinative polymers for reusable heterogeneous catalysts
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Hsiu‐Hao Hsu, Jia‐Qi Li, Gene-Hsiang Lee, Hsiang‐Chun Chang, Tsung‐Han Tu, Ching-Kai Lin, Chi-How Peng, Yu‐Jung Hsu, Yi-Liang Hsieh, and Yi-Hung Liu
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chemistry.chemical_classification ,chemistry ,Chemical engineering ,General Chemistry ,Polymer ,Heterogeneous catalysis ,Catalysis - Published
- 2019
14. Augmenter of liver regeneration regulates cellular iron homeostasis by modulating mitochondrial transport of ATP-binding cassette B8
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Teruki Sato, Jason S. Shapiro, Hossein Ardehali, Hsiang-Chun Chang, Xinghang Jiang, Justin Geier, Konrad T Sawicki, and Grant Senyei
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0301 basic medicine ,QH301-705.5 ,Science ,ATP-binding cassette transporter ,Mitochondrion ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,iron ,Mitochondrial myopathy ,Downregulation and upregulation ,medicine ,Animals ,Homeostasis ,Humans ,Oxidoreductases Acting on Sulfur Group Donors ,Biology (General) ,Inner mitochondrial membrane ,Mitochondrial transport ,Mice, Knockout ,030102 biochemistry & molecular biology ,General Immunology and Microbiology ,Chemistry ,General Neuroscience ,Cell Biology ,General Medicine ,medicine.disease ,mitochondrial protein import ,Cell biology ,mitochondria ,Protein Transport ,augmenter of liver regeneration ,Cytosol ,HEK293 Cells ,030104 developmental biology ,Medicine ,ATP-Binding Cassette Transporters ,Biogenesis ,Research Article ,Human - Abstract
Chronic loss of Augmenter of Liver Regeneration (ALR) results in mitochondrial myopathy with cataracts; however, the mechanism for this disorder remains unclear. Here, we demonstrate that loss of ALR, a principal component of the MIA40/ALR protein import pathway, results in impaired cytosolic Fe/S cluster biogenesis in mammalian cells. Mechanistically, MIA40/ALR facilitates the mitochondrial import of ATP-binding cassette (ABC)-B8, an inner mitochondrial membrane protein required for cytoplasmic Fe/S cluster maturation, through physical interaction with ABCB8. Downregulation of ALR impairs mitochondrial ABCB8 import, reduces cytoplasmic Fe/S cluster maturation, and increases cellular iron through the iron regulatory protein-iron response element system. Our finding thus provides a mechanistic link between MIA40/ALR import machinery and cytosolic Fe/S cluster maturation through the mitochondrial import of ABCB8, and offers a potential explanation for the pathology seen in patients with ALR mutations.
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- 2021
15. Author response: Augmenter of liver regeneration regulates cellular iron homeostasis by modulating mitochondrial transport of ATP-binding cassette B8
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Teruki Sato, Justin Geier, Konrad T Sawicki, Hossein Ardehali, Jason S. Shapiro, Xinghang Jiang, Grant Senyei, and Hsiang-Chun Chang
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Iron homeostasis ,Chemistry ,ATP-binding cassette transporter ,Mitochondrial transport ,Liver regeneration ,Cell biology - Published
- 2021
16. The Jumonji-C Histone Lysine Demethylase KDM3B Senses Cellular Iron to Regulate Anabolism Through mTORC1
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Jason Shapiro, Hsiang-Chun Chang, Zibo Zhao, Justin Geier, Elizabeth Bartom, Chunlei Chen, Yihan Chen, Adam De Jesus, Zohra Sattar, Farnaz Keyhani-Nejad, Tatsuya Sato, Lucia Ramos-Alonso, Antonia Maria Romero, Maria Teresa Martinez-Pastor, Shang-chuan Jiang, Shiv K. Sah-Teli, Liming Li, David Bentrem, Gary Lopaschuk, Issam Ben-Sahra, Thomas V. O'Halloran, Ali Shilatifard, Sergi Puig, Joy Bergelson, Peppi Koivunen, and Hossein Ardehali
- Published
- 2021
17. Augmenter of Liver Regeneration Regulates Cellular Iron Homeostasis by Modulating Mitochondrial Transport of ATP-Binding Cassette B8
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Hsiang-Chun Chang, Teruki Sato, Jason S. Shapiro, Hossein Ardehali, Konrad T Sawicki, Grant Senyei, and Xinghang Jiang
- Subjects
Cytosol ,Mitochondrial myopathy ,Downregulation and upregulation ,Chemistry ,medicine ,ATP-binding cassette transporter ,medicine.disease ,Inner mitochondrial membrane ,Liver regeneration ,Mitochondrial transport ,Biogenesis ,Cell biology - Abstract
Chronic loss of Augmenter of Liver Regeneration (ALR) results in mitochondrial myopathy with cataracts, however, the mechanism for this disorder remains unclear. Here, we demonstrate that loss of ALR, a principal component of the MIA40/ALR protein import pathway, results in impaired cytosolic Fe/S cluster biogenesis in mammalian cells. Mechanistically, MIA40/ALR facilitates the mitochondrial import of ATP binding cassette (ABC)-B8, an inner mitochondrial membrane protein required for cytoplasmic Fe/S cluster maturation, through physical interaction with ABCB8. Downregulation of ALR impairs mitochondrial ABCB8 import, reduces cytoplasmic Fe/S cluster maturation, and increases cellular iron through the iron regulatory protein-iron response element system. Our finding provides a mechanistic link between MIA40/ALR import machinery and cytosolic Fe/S cluster maturation through the mitochondrial import of ABCB8, and offers a potential explanation for the pathology seen in patients with ALR mutations.
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- 2020
18. Abstract 14395: Abnormal Regulation of P53-mTOR Pathway by MRNA-binding Protein ZFP36L2 in Peri-partum Cardiomyopathy
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Issam Ben-Sahra, Chunlei Chun, Warren A. McGee, Hossein Ardehali, Hsiang-Chun Chang, Jason S. Shapiro, Adam De Jesus, Hidemichi Kouzu, and Yuki Tatekoshi
- Subjects
Peripartum cardiomyopathy ,business.industry ,Mechanism (biology) ,Peri ,Cardiomyopathy ,Mrna binding ,medicine.disease ,Loss of function mutation ,Physiology (medical) ,Cancer research ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,PI3K/AKT/mTOR pathway - Abstract
Introduction: A loss of function mutation in the mRNA binding protein ZFP36L2 has been associated with congenital heart diseases in humans, although the mechanism remains unclear. Objectives: We sought to elucidate the role of ZFP36L2 in the heart using mice with cardiac-specific ZFP36L2 deletion. Results: Cardiac-specific Zfp36l2 knockout (cs-L2KO) female mice exhibit a dramatic phenotype in which the majority of mice die after repeated pregnancies due to heart failure. We performed RNA-seq in H9c2 cells with ZFP36L2 KD, and found the expression of multiple mTOR pathway genes were altered, including marked repression of Redd1 and Sesn2 . Consistent with the RNA-seq data, the activity of mTORC1 was increased in cs-L2KO mouse hearts and in ZFP36L2 KD H9c2 cells. Loss of TSC2 mitigated mTORC1 hyperactivity in ZFP36L2 KD cells, indicating that ZFP36L2 regulates mTORC1 activity through the TSC2 complex. Overexpression of REDD1 rescued increased mTORC1 activity with ZFP36L2 KD, suggesting that ZFP36L2 regulates mTORC1, in-part through REDD1. Under total amino acid starvation, we observed higher p-S6K T389 levels in ZFP36L2 KD cells, and SESN2 overexpression mitigated p-S6K T389 , indicating loss of ZFP36L2 also regulates mTORC1 through amino acid sensing. p53 is a transcriptional activator of both REDD1 and SESN2, and we found that ZFP36L2 was required to maintain p53 levels by directly destabilizing MDM2 mRNA. Accordingly, administration of Nutlin3, an MDM2 inhibitor, reversed the reduction in p53, REDD1 and SESN2 protein levels, and prevented the increase in S6K phosphorylation in response to ZFP36L2 KD. Next, we treated pregnant mice with rapamycin, and cs-L2KO mice treated with rapamycin displayed significantly improved cardiac function after delivery. Finally, we analyzed human heart samples from patients with peri-partum cardiomyopathy and found ZFP36L2 protein to be significantly decreased and p-S6K T389 levels increased, compared to healthy controls. Conclusions: Our studies demonstrate that ZFP36L2 regulates mTORC1 activity through modifying p53 stability, and that the disruption of this pathway induces peri-partum cardiomyopathy. Inhibition of mTORC1 hyperactivity with rapamycin can be a potential therapy for this disease.
- Published
- 2020
19. Hexokinase 1 cellular localization regulates the metabolic fate of glucose
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Hossein Ardehali, Justin Geier, Trenton Nicioli, Joshua S. Stoolman, Krishna V. Suresh, Samuel E. Weinberg, Lauren Goodman, Adam De Jesus, Kai Xu, Hsiang-Chun Chang, Paulina J Stanczyk, Chunlei Chen, Navdeep S. Chandel, Carolina M. Pusec, Arianne E. Rodriguez, Brian T. Layden, Issam Ben-Sahra, Jason S. Shapiro, Yihan Chen, Kriti P. Shah, and Farnaz Keyhani-Nejad
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Hexokinase ,biology ,Chemistry ,Nitrosylation ,Cell Biology ,Pentose phosphate pathway ,Mitochondrion ,Cell biology ,Mitochondria ,Pentose Phosphate Pathway ,chemistry.chemical_compound ,Mice ,Glucose ,stomatognathic system ,biology.protein ,Animals ,Glycolysis ,Flux (metabolism) ,Molecular Biology ,Glyceraldehyde 3-phosphate dehydrogenase ,Cellular localization - Abstract
The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative pathways, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. However, it is not known what determines the fate of G6P. HK1 contains an N-terminal mitochondrial–binding domain, but its physiologic significance remains unclear. We overexpressed full-length and truncated HK1 in tissue culture and generated mice lacking the HK1 mitochondrial-binding domain (ΔE1HK1). Although ΔE1HK1 mice displayed no overt phenotype, HK1 dislocation from the mitochondria increased glucose flux through the PPP, decreased flux below the level of GAPDH, and induced a hyper-inflammatory response to lipopolysaccharide. The mechanism for the increased PPP flux is through glycolytic block at GAPDH, which is mediated by binding of cytosolic HK1 with S100A8/A9 and increased GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed an increase in cytosolic HK1 and cytokine production, along with reduced GAPDH activity. Our data indicate that HK1 mitochondrial-binding alters glucose metabolism through regulation of GAPDH.
- Published
- 2022
20. Abstract 424: Loss of Sirt2 Protects Against Pressure Overload- and Ischemic Reperfusion Injury-induced Cardiac Dysfunction
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Chen Chunlei, Hossein Ardehali, Teruki Sato, Jason S. Shapiro, Hsiang-Chun Chang, and Xiaoyan Yan
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Pressure overload ,Ischemic reperfusion injury ,medicine.medical_specialty ,Physiology ,business.industry ,Internal medicine ,Cardiology ,Medicine ,Cardiology and Cardiovascular Medicine ,SIRT2 ,business ,Cardiac dysfunction - Abstract
Introduction: Sirtuins are NAD+ dependent deacetylases and critical regulators of energy metabolism and response to oxidative stress. Sirtuin2 (SIRT2) is a cytoplasmic member of the sirtuin family, and has been shown to regulate cellular iron homeostasis through deacetylation of nuclear factor erythroid-derived 2-related factor 2 (NRF2). However, whether SIRT2-NRF2 pathway is involved in the development of heart failure remains unknown. Methods and results: To investigate the functional role of SIRT2 in the response to cardiac stress, SIRT2 knockout (KO) mice and their littermate controls were subjected to pressure overload by transverse aortic constriction (TAC). SIRT2 KO had normal appearance and cardiovascular parameters at baseline. However, in response to TAC, Sirt2 -/- mice displayed resistance to the pathological hypertrophic response, whereas wild type (WT) mice developed cardiac hypertrophy and heart failure. In addition, SIRT2 KO mice displayed less cardiac damage after /reperfusion injury. SIRT2 knockdown in neonatal rat cardiomyocytes (NRCM) reduced reactive oxygen species (ROS) production and cell death after H2O2 treatment. Since cellular oxidative stress is one of major contributor of cardiac dysfunction caused by both I/R injury and pressure overload, we examined whether NRF2 is associated with SIRT2-mediated cardiac response to oxidative stress. Levels of NRF2 was upregulated in NRCM with SIRT2 knockdown and treated with H2O2 compared to wild type (WT) cells. Moreover, NRF2 is translocated into the nucleus and its anti-oxidant target proteins are upregulated in NRCM with SIRT2 knockdown. SIRT2 was also found to bind and deacetylate NRF2 directly as determined by co-immunoprecipitation studies. This led to a reduction of its nuclear translocation and transcriptional activity. Finally, knockdown of both SIRT2 and NRF2 diminished the effects of SIRT2 knockdown on ROS production and cellular damage. Conclusion: These results indicate that SIRT2 contributes to pressure overload and I/R injury induced heart impairment in mice, and promotes oxidative stress injury in cardiomyocytes via deacetylating NRF2 and altering its activity.
- Published
- 2020
21. Abstract 263: Loss of the RNA-binding Protein ZFP36L2 Results in Peri-partum Cardiomyopathy Through Dysregulation of the P53-mTOR Pathway
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Issam Ben-Sahra, Hidemichi Kouzu, Adam De Jesus, Jason S. Shapiro, Hsiang-Chun Chang, Yuki Tatekoshi, Perry J. Blackshear, Hossein Ardehali, and Paulina J Stanczyk
- Subjects
Physiology ,Chemistry ,Peri ,Cardiomyopathy ,medicine ,Cancer research ,RNA-binding protein ,Cardiology and Cardiovascular Medicine ,medicine.disease ,PI3K/AKT/mTOR pathway - Abstract
Introduction: A loss of function mutation in the mRNA binding protein ZFP36L2 has been associated with congenital heart diseases in humans, although the mechanism remains unclear. Objectives: We sought to elucidate the role of ZFP36L2 in the heart using mice with cardiac-specific ZFP36L2 deletion. Results: Cardiac-specific Zfp36l2 knockout (cs-L2KO) female mice exhibit a dramatic phenotype in which the majority of mice die after repeated pregnancies due to heart failure. We performed RNA-seq in H9c2 cells with ZFP36L2 KD, and found the expression of multiple mTOR pathway genes were altered, including marked repression of Redd1 and Sesn2 . Consistent with the RNA-seq data, the activity of mTORC1 was increased in cs-L2KO mouse hearts and in ZFP36L2 KD H9c2 cells. Loss of TSC2 mitigated mTORC1 hyperactivity in ZFP36L2 KD cells, indicating that ZFP36L2 regulates mTORC1 activity through the TSC2 complex. Overexpression of REDD1 rescued increased mTORC1 activity with ZFP36L2 KD, suggesting that ZFP36L2 regulates mTORC1, in-part through REDD1. Under total amino acid starvation, we observed higher p-S6K T389 levels in ZFP36L2 KD cells, and SESN2 overexpression mitigated p-S6K T389 , indicating loss of ZFP36L2 also regulates mTORC1 through amino acid sensing. p53 is a transcriptional activator of both REDD1 and SESN2, and we found that ZFP36L2 was required to maintain p53 levels by directly destabilizing MDM2 mRNA. Accordingly, administration of Nutlin3, an MDM2 inhibitor, reversed the reduction in p53, REDD1 and SESN2 protein levels, and prevented the increase in S6K phosphorylation in response to ZFP36L2 KD. Next, we treated pregnant mice with rapamycin, and cs-L2KO mice treated with rapamycin displayed significantly improved cardiac function after delivery. Finally, we analyzed human heart samples from patients with peri-partum cardiomyopathy and found ZFP36L2 protein to be significantly decreased and p-S6K T389 levels increased, compared to healthy controls. Conclusions: Our studies demonstrate that ZFP36L2 regulates mTORC1 activity through modifying p53 stability, and that the disruption of this pathway induces peri-partum cardiomyopathy. Inhibition of mTORC1 hyperactivity with rapamycin can be a potential therapy for this disease.
- Published
- 2020
22. Physical Gold Nanoparticle-Decorated Polyethylene Glycol-Hydroxyapatite Composites Guide Osteogenesis and Angiogenesis of Mesenchymal Stem Cells
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Chiung-Chyi Shen, Huey Shan Hung, Cheng-Ming Tang, Yi-Chin Yang, Chun-An Yeh, Shan-hui Hsu, Kai-Bo Chang, Hsiang-Chun Chang, and Hsien-Hsu Hsieh
- Subjects
mesenchymal stem cells ,Biocompatibility ,QH301-705.5 ,Chemistry ,Mesenchymal stem cell ,technology, industry, and agriculture ,hydroxyapatite ,Medicine (miscellaneous) ,Osteoblast ,Bone tissue ,Article ,General Biochemistry, Genetics and Molecular Biology ,physical gold nanoparticle ,Surface coating ,medicine.anatomical_structure ,Colloidal gold ,polyethylene glycol ,medicine ,Biophysics ,Surface modification ,Nanotopography ,Biology (General) - Abstract
In this study, polyethylene glycol (PEG) with hydroxyapatite (HA), with the incorporation of physical gold nanoparticles (AuNPs), was created and equipped through a surface coating technique in order to form PEG-HA-AuNP nanocomposites. The surface morphology and chemical composition were characterized using scanning electron microscopy (SEM), atomic force microscopy (AFM), UV–Vis spectroscopy (UV–Vis), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and contact angle assessment. The effects of PEG-HA-AuNP nanocomposites on the biocompatibility and biological activity of MC3T3-E1 osteoblast cells, endothelial cells (EC), macrophages (RAW 264.7), and human mesenchymal stem cells (MSCs), as well as the guiding of osteogenic differentiation, were estimated through the use of an in vitro assay. Moreover, the anti-inflammatory, biocompatibility, and endothelialization capacities were further assessed through in vivo evaluation. The PEG-HA-AuNP nanocomposites showed superior biological properties and biocompatibility capacity for cell behavior in both MC3T3-E1 cells and MSCs. These biological events surrounding the cells could be associated with the activation of adhesion, proliferation, migration, and differentiation processes on the PEG-HA-AuNP nanocomposites. Indeed, the induction of the osteogenic differentiation of MSCs by PEG-HA-AuNP nanocomposites and enhanced mineralization activity were also evidenced in this study. Moreover, from the in vivo assay, we further found that PEG-HA-AuNP nanocomposites not only facilitate the anti-immune response, as well as reducing CD86 expression, but also facilitate the endothelialization ability, as well as promoting CD31 expression, when implanted into rats subcutaneously for a period of 1 month. The current research illustrates the potential of PEG-HA-AuNP nanocomposites when used in combination with MSCs for the regeneration of bone tissue, with their nanotopography being employed as an applicable surface modification approach for the fabrication of biomaterials.
- Published
- 2021
23. Abstract 308: Role of Snf1-related Kinase as a Regulator of Chromatin Modifications and Dna-damage Response in Heart Injury
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Hossein Ardehali, Adam De Jesus, Paulina J Stanczyk, Zachary A. Zilber, and Hsiang-Chun Chang
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Heart Injury ,Physiology ,Kinase ,DNA damage ,Regulator ,Biology ,Cardiology and Cardiovascular Medicine ,Chromatin ,Cell biology - Abstract
Introduction: Altered DNA damage response (DDR) can result in phenotypic changes that share features with age-associated pathological conditions, including metabolic and cardiovascular abnormalities. Snf1-related kinase (SNRK) is a serine/threonine kinase that belongs to the AMPK family. Our recent data demonstrates that SNRK expression is upregulated in heart failure (HF) and low energy states and that SNRK improves cardiac mitochondrial efficiency and cell survival. Here, we assessed the hypothesis that in response to stress, SNRK translocates to the nucleus where it modulates nuclear processes to enhance DNA repair and ultimately reduces cardiomyocyte death. Results: We first showed that the nuclear distribution of endogenous SNRK in cardiomyoblast is enhanced under low nutrient and oxidative stress. Next, we performed global phosphoproteomics analysis on cells with overexpression of wild type SNRK and mutant kinase-dead SNRK (D158A). We found significant increase of several phosphopeptides involved in nuclear processes, in particular in the regulation of chromatin remodeling and DDR. SNRK downregulation resulted in an increase in nucleus volume and heterochromatin content, with increased nuclear dysmorphia when subjected to oxidative stress. Despite having lower expression of DDR signal effectors p53 and Mdm2, these cells accumulated higher levels of pH2AX (DDR marker) and displayed higher cellular death after oxidative stress, consistent with increased DNA damage. Etoposide treatment in SNRK knockdown cells failed to induce p53 levels despite pH2AX accumulation. Additionally, pharmacological stabilization of p53 protein through nutlin-3A treatment did not increase p53 in SNRK knockdown cells. These findings suggest that SNRK regulates p53 expression, thereby acting as a new modulator of DDR. Conclusions: Our results demonstrate increased nuclear localization of SNRK under stress conditions, and that SNRK regulates phosphorylation of nuclear proteins involved in chromatin remodelling and DDR. Thus, SNRK may induce its pro-survival cardiac functions through regulation of chromatin architecture and enhancing DDR. Those novel findings can contribute to development of new therapies against HF.
- Published
- 2019
24. Intravenous iron therapy in heart failure: a different perspective
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Hossein Ardehali, Hsiang-Chun Chang, and Kambiz Ghafourian
- Subjects
Heart Failure ,medicine.medical_specialty ,Anemia, Iron-Deficiency ,business.industry ,Anemia ,Perspective (graphical) ,MEDLINE ,Intravenous iron ,medicine.disease ,Ferric Compounds ,Heart failure ,Injections, Intravenous ,Hematinics ,Medicine ,Humans ,Cardiology and Cardiovascular Medicine ,business ,Intensive care medicine - Published
- 2019
25. Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2
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Lisa D. Wilsbacher, Hsiang-Chun Chang, David Gius, Athanassios Vassilopoulos, Seong Hoon Park, Paul W. Burridge, Konrad T Sawicki, Xiaoyan Yang, Jason S. Shapiro, Chunlei Chen, Meng Shang, Mitchell D. Knutson, Supak Jenkitkasemwong, Conrad L. Epting, and Hossein Ardehali
- Subjects
Transcriptional Activation ,0301 basic medicine ,NF-E2-Related Factor 2 ,Iron ,Gene Expression ,Biology ,SIRT2 ,Epigenesis, Genetic ,60602 Animal Physiology - Cell ,03 medical and health sciences ,Sirtuin 2 ,Gene expression ,medicine ,Animals ,Homeostasis ,Humans ,Viability assay ,Cation Transport Proteins ,Transcription factor ,Mice, Knockout ,Protein Stability ,Acetylation ,Hep G2 Cells ,General Medicine ,Metabolism ,Iron deficiency ,medicine.disease ,Cell biology ,HEK293 Cells ,030104 developmental biology ,Liver ,Biochemistry ,FOS: Biological sciences ,Sirtuin ,biology.protein ,Protein Processing, Post-Translational ,Research Article - Abstract
SIRT2 is a cytoplasmic sirtuin that plays a role in various cellular processes, including tumorigenesis, metabolism, and inflammation. Since these processes require iron, we hypothesized that SIRT2 directly regulates cellular iron homeostasis. Here, we have demonstrated that SIRT2 depletion results in a decrease in cellular iron levels both in vitro and in vivo. Mechanistically, we determined that SIRT2 maintains cellular iron levels by binding to and deacetylating nuclear factor erythroid-derived 2-related factor 2 (NRF2) on lysines 506 and 508, leading to a reduction in total and nuclear NRF2 levels. The reduction in nuclear NRF2 leads to reduced ferroportin 1 (FPN1) expression, which in turn results in decreased cellular iron export. Finally, we observed that Sirt2 deletion reduced cell viability in response to iron deficiency. Moreover, livers from Sirt2-/- mice had decreased iron levels, while this effect was reversed in Sirt2-/- Nrf2-/- double-KO mice. Taken together, our results uncover a link between sirtuin proteins and direct control over cellular iron homeostasis via regulation of NRF2 deacetylation and stability.
- Published
- 2019
- Full Text
- View/download PDF
26. Abstract 17382: Jumonji-C Histone Demethylases Are Cellular Iron Sensors That Control mTORC1 and Mitophagy
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Jason S Shapiro, Hsiang-Chun Chang, and Hossein Ardehali
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Iron is an essential nutrient and is critical for cellular growth and metabolism. Here, we delineate a novel mechanism by which iron alters amino acid homeostasis and mTOR activity by remodeling the cellular epigenetic landscape. We find that iron deficiency inactivates Jumonji-C domain containing histone-demethylases, resulting in histone hyper-methylation and silencing of the leucine transporter LAT3 and obligatory mTORC1 cofactor RAPTOR. Additionally, we identify that mTOR-mediated regulation of RNA stability through tristetraprolin (TTP) is a novel and requisite step in selective-autophagy. In the absence of TTP, mitochondria damaged by the loss of iron cannot undergo fission, rendering the mitochondria too large for engulfment and subsequent recycling. Accumulation of damaged mitochondria leads to defective oxidative metabolism and impairs hepatic gluconeogenesis in response to fasting. These studies uncover a novel pathway that integrates iron sensing with cellular metabolism, mitochondrial dynamics and autophagy.
- Published
- 2018
27. Reduction in mitochondrial iron alleviates cardiac damage during injury
- Author
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Meng Shang, Sathyamangla Vn Prasad, Jason S. Shapiro, Anita Thakur, Tatsuya Sato, Ting Liu, Rongxue Wu, Hossein Ardehali, Hsiang-Chun Chang, Konrad T Sawicki, and Chunlei Chen
- Subjects
0301 basic medicine ,Mitochondrial ROS ,Iron ,Ischemia ,Cardiomyopathy ,heart failure ,Myocardial Reperfusion Injury ,ischemia ,Mitochondrion ,Biology ,Cardiovascular System ,03 medical and health sciences ,medicine ,Animals ,Humans ,Research Articles ,chemistry.chemical_classification ,Reactive oxygen species ,Metabolism ,medicine.disease ,ischemia/reperfusion ,Electron transport chain ,Mitochondria ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Biochemistry ,Heart failure ,Molecular Medicine ,Cardiomyopathies ,Reactive Oxygen Species ,Research Article - Abstract
Excess cellular iron increases reactive oxygen species (ROS) production and causes cellular damage. Mitochondria are the major site of iron metabolism and ROS production; however, few studies have investigated the role of mitochondrial iron in the development of cardiac disorders, such as ischemic heart disease or cardiomyopathy (CM). We observe increased mitochondrial iron in mice after ischemia/reperfusion (I/R) and in human hearts with ischemic CM, and hypothesize that decreasing mitochondrial iron protects against I/R damage and the development of CM. Reducing mitochondrial iron genetically through cardiac‐specific overexpression of a mitochondrial iron export protein or pharmacologically using a mitochondria‐permeable iron chelator protects mice against I/R injury. Furthermore, decreasing mitochondrial iron protects the murine hearts in a model of spontaneous CM with mitochondrial iron accumulation. Reduced mitochondrial ROS that is independent of alterations in the electron transport chain's ROS producing capacity contributes to the protective effects. Overall, our findings suggest that mitochondrial iron contributes to cardiac ischemic damage, and may be a novel therapeutic target against ischemic heart disease.
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- 2016
28. Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21
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Jason S. Shapiro, Brian N. Finck, Marina Bayeva, Hsiang-Chun Chang, Jason A. Wertheim, Perry J. Blackshear, Adam De Jesus, Konrad T Sawicki, and Hossein Ardehali
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0301 basic medicine ,Male ,medicine.medical_specialty ,FGF21 ,Glucose uptake ,medicine.medical_treatment ,Tristetraprolin ,Adipose tissue ,030209 endocrinology & metabolism ,Diet, High-Fat ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Insulin resistance ,Downregulation and upregulation ,Adipose Tissue, Brown ,Internal medicine ,medicine ,Animals ,Humans ,Insulin ,RNA Processing, Post-Transcriptional ,Adiponectin ,Chemistry ,General Medicine ,medicine.disease ,Fibroblast Growth Factors ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Liver ,Insulin Resistance ,Gene Deletion ,Research Article - Abstract
The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.
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- 2018
29. mRNA-binding protein tristetraprolin is essential for cardiac response to iron deficiency by regulating mitochondrial function
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Issam Ben-Sahra, Deborah J. Stumpo, Paul T. Schumacker, Ting Liu, Hsiang-Chun Chang, Hossein Ardehali, Lucía Ramos-Alonso, Konrad T Sawicki, Xinghang Jiang, Sergi Puig, Marina Bayeva, Hidemichi Kouzu, María Teresa Martínez-Pastor, Perry J. Blackshear, Chunlei Chen, Sumeyye Yar, Jason S. Shapiro, and Tatsuya Sato
- Subjects
0301 basic medicine ,Cardiac response ,Cardiac function curve ,Iron-Sulfur Proteins ,Tristetraprolin ,Mitochondria, Heart ,Cell Line ,03 medical and health sciences ,Electron Transport Complex III ,Mice ,medicine ,Animals ,chemistry.chemical_classification ,Mice, Knockout ,Reactive oxygen species ,Multidisciplinary ,NDUFS1 ,Myocardium ,NADH Dehydrogenase ,Iron deficiency ,Iron Deficiencies ,medicine.disease ,Cell biology ,030104 developmental biology ,chemistry ,PNAS Plus ,Coenzyme Q – cytochrome c reductase ,Oxidation-Reduction ,Function (biology) - Abstract
Cells respond to iron deficiency by activating iron-regulatory proteins to increase cellular iron uptake and availability. However, it is not clear how cells adapt to conditions when cellular iron uptake does not fully match iron demand. Here, we show that the mRNA-binding protein tristetraprolin (TTP) is induced by iron deficiency and degrades mRNAs of mitochondrial Fe/S-cluster-containing proteins, specifically Ndufs1 in complex I and Uqcrfs1 in complex III, to match the decrease in Fe/S-cluster availability. In the absence of TTP, Uqcrfs1 levels are not decreased in iron deficiency, resulting in nonfunctional complex III, electron leakage, and oxidative damage. Mice with deletion of Ttp display cardiac dysfunction with iron deficiency, demonstrating that TTP is necessary for maintaining cardiac function in the setting of low cellular iron. Altogether, our results describe a pathway that is activated in iron deficiency to regulate mitochondrial function to match the availability of Fe/S clusters.
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- 2018
30. Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution
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Raechel Harnoto, Morgan C. Anderson, Amy Z. Xu, Heather Hedeen, Arnaldo J. Santiago-Sanabria, Brandy L. Hammond, Kenneth Saville, Ross D. Kooienga, Christopher Chesley, Robert W. Morris, Aubree T. Gillis, Brittney Offenbacker, Katherine C. Palozola, Trisha Tomkins, Nicole Yu, Matthew Kwong, Megan E. Aldrup, Jordan E. Kus, Chelsey Friedrichs, Kenneth Stapleton, Carly E. Pelchen, Norma Chamma, Joshua F. Machone, Danielle Kulich, Andre Kennedy, Matt J. Crowley, Daniel Broomfield, Adeola Adebayo, Nicolas Ragland, Shady Messiah, Jonathan Misch, Meghan B. Rooney, Eva N. Rubio-Marrero, Will Sherrill, Joyce Stamm, Rachel R. Leads, Lindsey Shantzer, Alexis J. Scott, Andrew W. Waggoner, Kristen M. Cooper, Adam Haberman, Carmen A. Watchinski, Marcos A. Perez, Lisa Kadlec, Kiara N. Medina-Ortega, Kayla Chapman, Cheryl Bailey, Nicholas Fazzio, Insun Chong, Lasse Schmidt, Darla M. Balthaser, Megan DeShetler, Jien Shim, Anna Rogers, Chris Uitvlugt, Bryan Yarrington, Ruth A. Howe, Andrea Ochoa, Gregory J. Mullen, Young Lu Kim, Olivia L Knowles, Kevin M. Levine, Matthew M. Villerot, Thomas J. Rose, Jonathan E. Smith, Sukhjit Kaur, Roshni Patel, Olivia Plante, Tenzin Choeying, Jennifer R. Ramthun, Tiffany Y. Y. Choi, Michael Rahimi, Guzal Khayrullina, Lauren R. Boudreaux, James E. J. Bedard, Brian A. Dow, Christopher A. Louie, Kenneth S. Smith, Joannee Zumkehr, Marcus Gostelow, Melissa A. Tache, Tiffany Dai, Joan D. Zambrana-Burgos, Lauren R. Meyer, Carter Brown, Adam Brown, Travis Lamb, Carissa Belella, Hannah Gilman, David DuPuis, Ramón E. Rivera-Vicéns, Priyanka Naik, Anna L. Shipman, Jad El-Adaimi, Eric Spencer, Jonathan D. Marra, Melissa D. Patao, Sharon Ibarra, Jiayu Zhang, Ashley Vetor, Bobbi Botsford, Jenifer Winters, Nelson A. Valentín-Feliciano, Lauren M. Robinson, Christopher R. Macchi, Jennifer Hernández-Muñiz, E. Gloria C. Regisford, Jaelyn L. Johnson, Cory M. Dauphin, Tezin A. Walji, Matthew A. Zaborowicz, Stacey Winkler, Shannon M. Lowell, Marly R. McCracken, Andrew Adams, Lindsay A. Spaeder, Matthew W. Wolski, Adrese Kandahari, Fabiola Robles-Juarbe, Bryce A. Turner, Ángel L. Laboy-Corales, David T. Watson, Elaine J. Durchholz, Vanessa Rodriguez, Emily J. Teepe, Alaina C. Conturso, Eric Nyabeta Onsarigo, Tijana Martinov, Rohit Venkat, Charles R. Hauser, Priya Srikanth, Marwan Ibrahem, Karl E. Smith, Jessica M. Tucci, Ethan J. Brock, Aparna Sreenivasan, Jasmine Hales, Brianna K. Barnard, Andrew P. Stein, Jessica G. Thomas, Mallory Perella, Lorraine Rodriguez-Bonilla, Shekerah Primus, Zachary D. Moore, Caitlin M. Ament, Amber N. Hare, Brad Pamnani, Eugenia A. Soliterman, Christina Paluskievicz, Yashira M. Valentín-Feliciano, Alexandra K. Eckardt, Anya Goodman, Joseph W. Noynaert, Ashlee G. Johnson, Tyneshia C. P. Henry, Camille D. Ratliff, Ian O. Chase, Michel A. Conn, Jessica Koehler, Daniela Martiniuc, Allison J. Schepers, Megan B. Vylonis, Chrystel Dol, William Dirkes, Michelle S. Rivera-Llovet, Susana Rodríguez-Santiago, Heather L. Eisler, Mary L. Preuss, Daymon Peterson, Martin G. Burg, Aaditya Khatri, John R. Woytanowski, Holly Schiedermayer, Dara Cohn, Leah E Waldman, William M. Morris, Sharon C. Ehret, Marianna Defendini-Ávila, Jessica Fese, Suzette M. Arias-Mejias, Anna Kammrath, William D. Barshop, Edwin G. Ramírez-Aponte, Luis A. Jimenez, Carolina Marques dos Santos Vieira, Cody D. Kern, Francheska M. Delgado-Peraza, Tiffany Wan, Janice L. Krumm, Osagie Ighile, Eric D. Sassu, Jess M. Darusz, Laura Rodela, Daniel S. Nicolas, Shubha Govind, Mary Miller, Joseph E Marcus, Jason Pollack, Rostislav Castillo, Daniel Coomes, Matthew J. Borr, Diana Pérez-Afanador, Lucas A. Watson, Hannah C. Koaches, Amber Quintana, Faith H. Kung, Cameron B. Harris, Bridget M. Janssen, Cristina Zambrana-Echevarría, Jennifer K. Jones, Ian Dobbe, Benjamin M. Lewis, Lena N. Lupey, Julia A. Hilbrands, Cristina Montero Diez, Jorge L. Santiago-Ortiz, Dustin S. Woyski, Sandy D. Mach, Joseph Perez-Otero, Karim A. Sharif, Carlos Mendoza, John D. Fitzgibbons, Nelson H. Knudsen, Christy MacKinnon, Hayley M. Faber, Kwabea Agbley, Michelle Heslop, Olivia Cyrankowski, Priscilla Rodriguez, Melissa Jones, Jean M. Strelitz, Ryan A. Grove, Rachel A Greenstein, Michael Murillo, Elizabeth Greiner-Sosanko, Ciani Jean Sparks, Darryl McFarland, Franca G. Rossi, Heran Gebreyesus, Chris Kay, Danielle Ladzekpo, Chris Harward, Jordan S. Christie, Consuelo J. Alvarez, Elaine V. Morlock, Geoff Scott, Kelsey Hockenberger, Sepo Musokotwane, Adam Fearnow, Lauren J. Keny, Alaina J. Grantham, Evangelina Reza, Mike Colgan, Melanie K. Regan, Stephanie J. Potocny, Sasha L. Dorsett, Tara Skorupa, Valerie M. Gónzalez-Pérez, Vinayak S. Nikam, Anne C. Meier, Varun Sundaram, Helen B. Rankin, Andrew B. Nylander, Mariela Gines-Rosario, Laurell MacMillian, Jeannette M. Osterloh, Robert H. Allen, Melanie A. Smith, Sarah J. Spencer, Cheri M. Ackerman, Jeffrey L. Poet, Amanda J. Hay, Isaac O. Armistead, Laura K. Reed, Don W. Paetkau, Bib Yang, Enid M. Quintana-Torres, Kathryn L. Golden, Lauren A. DiLorenzo, Alen Ramic, Mark T. LeBlanc, Carl J. Minniti, Robert J. Bailey, Kristen M. Thomsen, Ashley L. Adams, Chad A. Koplinsky, Eliezer O. Perez-Colomba, Nicole A. Howey, Katie A. TerMeer, Stephanie Intriago, Christina N. Kufel, Mary Waters, Bo Liu, Thomas J. Bahr, Ashley R. Miller, Claire Pattison, Morgan R. Light, Amy T. Hark, Jennifer S. Doty, Catherine M. Mageeney, Adam J. Ronk, Nadezhda Fefelova, Andrew R. Armstrong, Maida Chen, Elizabeth Macias, Kim M. Chau, Paul Bilinski, Trevor G. Floyd, Cassidy T. Lee, Jenna C. Tenney, Bob Gardner, Patricia Ortiz-Ortiz, Elizabeth S. Jewell, Gabi Lucas, Brandon Lee, Jenifer N. Jarrell, Jimmy Hsiang-Chun Chang, Lorraine Malkowitz, Ulises Marrero-Llerena, Gabriel Stancu, Matthew R. Unzicker, Andrea P. Burgos-Bula, Michelle L. Miller, Elisandra Rivera, Kate Bagaeva, Jessica W. Polk, Jordan E. Carney, Maureen Corrielus, Jana Nietmann, Jeff Howenstein, Elizabeth Kiernan, Sabya A. Rauf, Brandon M. Katz, Elizabeth C. Nordman, Devon Shallman, Eric M. Clark, Lenin Lopez, Karen J. Kraftmann, Leslie Guadron, Julia Kuhn, Allison R. Schneiter, Satish C. Bhalla, Emily J. Howell, Blair Undem, Jeffrey S. Thompson, Arelys Flores-Vazquez, John Kiley, Cody M. Morrow, Joseline Serrano-González, John Mark Knepper, Christopher Beck, Calise Debow, Anna L. Smith, Angelica Garcia, Shelbi Christgen, Shadie Emiah, Tammy Mazur, Rachel E. VanDyken, Frank R. Soto delValle, Zachary Nichols, William R. Kennedy, Ameer Zidan, Douglas A. Herrick, Thomas Q. Xu, Elizabeth Shoop, Jessica A. Kampmeier, John M. Kerber, Caitlin Pozmanter, Emily L. Hong, Frederic J. Deuschle, Allyson B. Rivard, William Neutzling, Joseph V. Moran, Benjamin K. Johnson, Jacob Jipp, Shannon R. McCartha, Abby Vrable, Z. Goodwin, Suchita Rastogi, Alyssa M. Newman, Lionel Ortiz-Fuentes, Arjun A. Anilkumar, Bryan M. Hennessy, Hui-Min Chung, Katie L. Goeller, Carlos E. Santos-Ramos, Adam Dillman, Christine D. Wilson, Sarah J. Peacock, Andrew J. Kim, Carol I. Morales-Caraballo, Briana Brinkley, Justin Alldredge, Rebecca Krock, Kristen C. Davis, David Dunbar, Joshua L. Manghelli, Erica K. Earl, Katherine Gavinski, Sheryl T. Smith, Portia Mason, Lindsay J. Hoogenboom, Jessen T. Havill, Sonya G. Méndez-Castellanos, Darrin T. Schultz, Katherine J. Faber, Allison O’Rouke, Emily G. Miller, Yara Ashrawi, Curtiss E. Lane, Saryleine Ortiz-DeChoudens, Michael W. Sandusky, Andrew Montgomery, Rita Kabaso, Todd Aronhalt, Jonathan D. Foust, Jorge Ruiz, Eric Helmreich, Todd T. Eckdahl, Charlotte Lea, Kevin Coulson, Kristin M. French, Kate A. Woodard, Brandon J. Burkhart, Kylie McNeil, Curtis R. Edwards, Jimmy Ma, Darcie D. Elder, Tia DiTommaso, Nicholaus Monsma, Sarah A. Jelgerhuis, Stephanie J. Adams, Nichole Rigby, Heather L. Holderness, Charlotte Williams, Megan Donegan, Taylor S. Harding, Javier O. Martinez-Rodriguez, Sandeep Venkataram, Tiffany Wong, Anika Toorie, Jenny L. Rose, Ashley S. Brown, Sarah A. Popelka, Matthew Williams, Julie Bryant, Sarah C. R. Elgin, Sonali Kumar, Joshua Burkhardt, William J. Puetz, Erica L. Alvendia, Richard A. Tumminello, Kesley Parry, Joshua R. Smith, Ashley F. Custer, Carlos E. Ortiz, Yedda Li, April E. Bednarski, Simon Ng, Max Mandelbaum, Arlene J. Hoogewerf, Chelsea A. Walker, Ryan S. Lee, Jeannette Wong, Isabella Theresa Felzer-Kim, Harrison Friedman, Megan Bourland, Luis R. Colón-Cruz, Lucy Liu, Nicole C. Olson, Yi Ren, Adam P Lousararian, José M. Cruz-García, Charlie Manchee, Kyle Zoll, Kristina M. Stemler, Juliana Belén-Rodríguez, Ashley S. Timko, Jane Lopilato, England Raimey, Amy D. Melton, Joshua D. Forsyth, Christopher D. Savell, Himabindu Reddy, Alica B. Allen, Amanda Maffa, Daniel W. Cassidy, Luciann Bracero-Quiñones, Eric Lemmon, Justina R. Bartling, Bradley J. Ogden, Petros Svoronos, Mary Spratt, Lisa Sudmeier, Héctor A. Martell-Martínez, James F. Geary, Bridget J. Sessions, Christopher Campana, Kaitlyn A. Downey, Seth G. Dawson, Daniella Menillo, Casey Hanson, James M. Bellush, Justin A. Gonzales, Roy Song, Karvyn Torchon, Betsy Hoover, Michael Closser, Lacey Neufeld, Micah Shelton, Benjamin R. Does, Juan Carlos Martínez-Cruzado, Jordan S. Baumgardner, Nicole Chichearo, Mary T. Reilly, Colleen V. Kelley, Monica Yalamanchili, Dawn Lau, Abbie Morgan, Alyssa Cifelli, Milton R. Herrold, Ambreen Khan, James Messler, Kyle Westphal, James L. Kehoe, Juliana A. Wurzler, Garrett Salzman, Tracy Wang, Charlene Emerson, Lyndsey A. Reynolds, Alysha Moretti, Marita K. Abrams, Mara G. Cole, Michael B. Schultz, Samantha Cruz, Natalie Ngai, Nadia Safa, Vicente Velasquez, Ashley Townsend, Jonathan L. Crooke-Rosado, Amber M. Gygi, Ishwar S. Gill, Christopher McLaughlin, Dorianmarie Vargas-Franco, Alissa Beckett, Samantha Vue, Nadine L. Rossi, Justina Chinwong, Ryan Michael Rempe, Trip Freeburg, Amy J. Johnson, Omolara Glenn, Jade Lea Rekai, Hashini Gunasinghe, Vivienne Echendu, Marshall Strother, Morgan Baker, Christopher D. Smith, Paolo A. DaSilva, Noelle Delacruz, Tiara Tirasawasdichai, Yakov Shevin, Wilfried Guiblet, Shane M. Patao, Peterson R. Cullimore, Giancarlo F. Garbagnati, Adam E. Musick, Sarah C. Butzler, Jonathan D. Presley, Ana I. Correa-Muller, Christopher D. Shaffer, Chunguang Du, Ryan D. Mitchell, Jonathan P. Rennhack, Barbara L. Hopkins, Mary E. Shaw, Jessica E. Hill, Jeremy N. Wong, Anna Kim, Christopher B. Khoury, Julia Chapman, Amanda T. Mercer, Jessica A. Shuen, Joyce H. Lau, I.N. Falk, Sunil Rathore, Christopher J. Jones, Laura Simone Bisogno, Nighat P. Kokan, Paul Yenerall, Amber L. Price, Kelsey T. Bushhouse, Stephen L. McDaniel, Andrew P. Drake, Johnathan D. English, Sampson K. Boham, Robert A. Herbstsomer, Daniel S. Fosselman, Kevin Babilonia-Figueroa, Matthew Simon, Anne G. Rosenwald, Bryan J. Rupley, Heather Cohen, Victoria Scala, Avery B. Cromwell, Christopher E. Blunden, Yelena P. Davis, William B. Armstrong, Kristine Ostby, Joanna Haye, Lauren M. Wysocki, Lena Christiansen, Allison A. Throm, Sarah Flohr, Matthew Wawersik, Rebecca J. Cotteleer, Kristen R Ramirez, Dontae A. Jacobs, Sarah Woehlke, Gregory S. Messenger, Soham Aso, Nicole Clarke-Medley, Bryant R. Swanson, Lindsay K. Brouwer, S. Catherine Silver Key, Stephanie Zarrasola, Michael S. Salgado, Dong K. Rhee, Mai Abdelnabi, Eve VanEck, Jeremy Buhler, Sarah Kong, Turner Conrad, Jennifer Roecklein-Canfield, Marykathryn Tynon, Brian J. Maniaci, Alexa M. McDonough, Ivan G. Llavona-Cartagena, J. Devin Spencer, Todd D. Johnson, Azita Bashiri, Kimberley Ramsey, Mike Polen, Hien P Nguyen, Seantay D. Patterson, Lucia Wande, Nicholas U. Schwartz, Han Yuan, Albeliz Santiago-Colón, Joseph Medina, Samuel Thomas Crowley, Emma Shoemaker, Alex J. Feliciano-Cancela, Alexander J. Kujawski, Lillyann Asencio-Zayas, Gentry L. Pickett, Matt J. Randazzo, Erica Stagaard, Kristin M. LaForge, Gabriela A. Llaurador-Caraballo, Anastasia K. Yemelyanova, Alan Tseng, Erika E. Menyes, Julie Azarewicz, Christa Burke, Samuel I. Smith, Nazanin Ghavam, Carolina Gomez, Cameron Fick, Anthony Pinto, Lindsay Rios, Gary A Kuleck, Ashley Rich, Kayla A. Florian, Martin N. Cheramie, Yuki Kwan Wa Shum, Atlee Baker, LaJerald Augustine, Alyson Greenwell, Rasleen K. Saluja, Jason S. Macias, Wesley W. Winn, Samantha M. Schmuecker, Michelle E. M. Eisen, Pedro Benitez, Jeanette Hauke, Nora C. Goscinski, Justin R. DiAngelo, Carter T. Docking, David D. Xiong, Brittany D. Pasierb, Matt Van Camp, Yin Zheng, Nikie L. McCabe, Emily Reed, Katie Homa, Kimberly S. Kolibas, Elizabeth A. Karaska, Grace A. Dougherty, John P. Fanning, Michael Fasano, Joseph E. Sable, Robert W. Schulz, San Francisco Nguyen, Michael L. Rojas-Vargas, Kierstin L. Naylor, Emily Peoples, Jessica Neely, Lejla Cesko, Brionna D. Davis-Reyes, Roxanne Banker, Amanda K. Tilot, Jordan P. Brand, William H. Newhart, Lauriaun Johnson, Michelle M. Giddens, Nicole B. Clark, Anant Agarwalla, Thomas F. Minton, Dana W. Brooks, Amanda D. Garrett, Bethany M. Klett, Kristin M. Starkey, Antoinette E. Fafara-Thompson, Michael R. Rubin, Jonathon M. Benson, Erica Enoch, Amanda M. Damsteegt, Zackary W. Scott, Elisabeth A. Kelly, Jason M. Barnett, Wilson Leung, Luke J. Rodriguez-Giron, Krishna C. Mudumbi, Francis J. May, Nadyan M. Vargas-Barreto, Geeta Statton, José L. Torres-Castillo, Sarah Hirsch, Rachel M. Reem, Linghui Li, Deirdre Robinett, Jason Caronna, Abneris E. Rodríguez-Laboy, Samantha Lawrence, Katherine R. Reynolds, Corinne Weeks, Allison M. Sterling, Chun Leung Ng, Roman E. Ramirez, Daron C. Barnard, Leming Zhou, Eric P. Spana, John A. Toth, Alvin Lu, Krizia C. Menéndez-Serrano, Jonathan M. Heckman, Ben Chlebina, Matthew C. Fadus, Helmet T. Karim, Shailly Gaur, Timothy R. Jelsema, Nicholas Keysock, Thomas J. Carr, Zach Fusco, Evan M. Verbofsky, Monal Naik, Amanda H. Flores, Kristin A. Knouse, Olga R. Kopp, Elizabeth Feenstra, Edward P. Sweeney, Christen Johnson, Justin Crawford, Damian Urick, Victor W. Mullen, Carrie A. Dunham, Gabriella A. DeMichele, Mengyang Sun, William Harrington, Jessica M. Bodenberg, Xavier A. Collado-Méndez, T. Aaron Wiles, Michelle K. Powers, Phillip J. Minnick, Lourdes N. Irizarry-González, Valeria Silva, Steven Ovu, Nik Kolba, Peter Lindbeck, Jerome M. Molleston, Ifeanyi Obiorah, David Carranza, Lauren R. Beck, Alina M. Tamayo-Figueroa, Elaine R. Mardis, Rachel N. Lippert, Ingrid T. Rivera-Pagán, Mahdi Soos, Trung T. Nguyen, Megan Martinez, Van Kim, Benjamin L. Danner, Randall J. DeJong, Melissa M. Trieu, Andrea M. Senquiz-Gonzalez, Mary Grace Schueler, Emily E. Magnuson, Lesley E. Jackson, Hendrick Pagán-Torres, Fareed Sanusi, Dana Koenig, Vidya Chandrasekaran, Chinmoy I. Bhatiya, Dongyeon Kim, Paul J. Overvoorde, Reece Watson, Jennifer Schottler, Devry Lin, Jim Youngblom, Taylor Schauder, Nigel Madden, Isabel Valdez, Thomas John Reynolds, Kelly M. Deranek, Anne A. Welker, Jackie X. White, Nicole C. Riddle, Jacob Pfeil, Aldo Heredia-Negrón, Christine Langner, Tao Jian He, Jonathan P. Mecoli, Lissett Mayorga, Scott Chiang, Rishi Singhal, Julia C. Peairs, Michael Quach, Anne M. Eime, GiNell Elliott, Meleah J. Gross, Melissa Drewry, Julia A. Emerson, Anthony K. Lambright, Isaac Appiah, Gregory M. Robertson, Nathaniel Regenold, Philip Pham, George Odisho, Alexi Archambault, Matthew Dothager, Shana M. Baldassari, Paul J. Lee, Callie R. Merry, Jesse R. Farek, Archana Tare, Srebrenka Robic, William Vernon, Tam Vuong, Bethany Grace Bonifield, Katrina Thistle, Rose M. Dowd, Noor Tazudeen, Jennifer Weaver, Manpreet Kaur, Nicole M. Caesar, Yi Zhang, Michael C. Cristostomo, Albert Tzeng, Kayla Vondy, Emily Perling, Ramiro A. Chavez, Lanor S. Horton, Matt Kroll, Levent H. Beken, Justin R. Starcher, Sam Asinof, Nathalia M. Cruz, Eunice George, Adam T. Morrow, Heather Milnthorp, Cheryl Mazzeo, Kristen R. Hatfield, Anna L. Boudoures, Ashley A. Tewilliager, Edna P. Tascón-Peñaranda, Vilma F. Huerta, Sarah Tuberty, Mallory A. Williams, Rachel E. Weber, Sarah Spencer, Emily C. Leatherman, Yuying Gosser, Steve DeFazio, Patrick Ng, Jeri Sparks, Pavan Bhat, Mindy E. Bower, Jordan E. Matthews, Cyrus E. Kuschner, Anne Bertolet, Matt Kusner, Thomas C. Giarla, Jessica Penn, Gerard P. McNeil, Mariam Meghdari, Michael J. Wolyniak, Matthew Juergens, Karla I. Velázquez-Soto, Maria Kaisler, Jeanine Schibler, Alexis Nagengast, Susan Parrish, Frances Marín-Maldonado, Shiv Mohini, Jessica King, Danny Mammo, Katherine S. Harker, Allyson P. Hawkins, Kelly Drumm, Jennifer A. Lammers, Allyson P Mallya, Ashley Bryant, Katie Weihbrecht, Pete Wendland, Gabriela V. Bernal-Vega, Nestor A. Gutierrez, Armando G. Bermudez-Capo, Luke R. Salbert, Kirk Haltaufderhyde, Michelle L. Kappes, Mary A. Smith, York Chen, Miguel Vélez-Vázquez, Brittany E. Plescher, Francis D. Beauchamp-Pérez, Alyssa Ward, Andrea N. Clary, Don Foret, Mitchell J McDonald, Mariela Colon-Vazquez, Amanda L. Blaker, Hao Yang, James Z. Liu, Austin B. Limle, Henry Huang, Luis Vilanova-Velez, Edgar Garibay, Philip J. Freda, Laura L. Mays Hoopes, Maureen S. Hammond, Marian M. Kaehler, Rebecca Shuford, Ray Sunjed, Cynthia K. Hanson, Marielle VanderVennen, Idaliz M. Martínez-Traverso, Jack Y. Yu, Spencer L. Franchi, Michael Snavely, John E. Anderson, Lainey S. Rubin, Kelly K. Jones, Stephanie F. Mel, Stacey Lytle, Danny L. Tran, Chelsea R. Barberi, Max Mian Liu, Eric A. Nollet, Sarah E. Muller, Diana Norton, John M. Braverman, Thu A. Phan, Nelson Membreno, Colin Khoshabian, John Gooch, Cassandra Kubricky, Priscila M. Rodríguez-García, Anna Wylie, Diana L. E. Johnson, Anna K. Unruh, Deborah Hammett, Jon Sarezky, Marie Brown, Carolina Riascos-Cuero, Emily J. Diekema, Emmy E. Ogawa, Miranda Chavez, Zuzana Kocsisova, Dennis Revie, Anniken M. Lydon, Peter A. Cognetti, Ashley A. Collins, Tariq Abusheikh, Erin K. Luippold, Kevin Myirski, Brian O. Rodríguez-Echevarría, Haley J. Plasman, Lara Baatenburg, Jesse Hendriksma, Christopher R. Knob, Max Semon, Cassandra Farrar, Xiao Zhu, Ali Dobbe, Marie-Isabelle B. Seydoux, Griffin Sadovsky, Shreya Prasad, Victoria Newcomb, Chad Gier, Dmitri Serjanov, Jules Wellinghoff, Maxwell T. Smith-Gee, and Alexandra H. Scoma
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Transposable element ,Codon Adaptation Index ,Euchromatin ,Heterochromatin ,transposons ,evolution of heterochromatin ,Investigations ,Genome ,Evolution, Molecular ,03 medical and health sciences ,gene size ,0302 clinical medicine ,melting characteristics ,Species Specificity ,codon bias ,Genetics ,Animals ,Drosophila Proteins ,Selection, Genetic ,Codon ,Molecular Biology ,Genetics (clinical) ,030304 developmental biology ,Polytene Chromosomes ,Repetitive Sequences, Nucleic Acid ,Gene Rearrangement ,0303 health sciences ,biology ,Computational Biology ,Molecular Sequence Annotation ,Gene rearrangement ,Exons ,Genomics ,biology.organism_classification ,Introns ,Drosophila melanogaster ,Codon usage bias ,DNA Transposable Elements ,Drosophila ,030217 neurology & neurosurgery - Abstract
The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.
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- 2015
31. The Good Neighbor
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Sumeyye Yar, Hossein Ardehali, and Hsiang-Chun Chang
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medicine.medical_specialty ,Physiology ,Type 2 Diabetes Mellitus ,Adipose tissue ,030209 endocrinology & metabolism ,Inflammation ,White adipose tissue ,030204 cardiovascular system & hematology ,Biology ,medicine.disease ,Systemic inflammation ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,Endocrinology ,chemistry ,Internal medicine ,Adipocyte ,medicine ,medicine.symptom ,Cardiology and Cardiovascular Medicine - Abstract
The prevalence of obesity is rising globally, and the United States has one of the highest obesity rates in the world: ≈17% of the young and >33% of adults are obese.1 Obesity is associated with chronic low-grade systemic inflammation, which is considered a critical underlying factor in the development of insulin resistance (IR).2 IR is a major risk factor for type 2 diabetes mellitus (T2DM) and cardiovascular disease.3 In the development of obesity, white adipose tissue, particularly the abdominal adipose tissue, is the key site that mediates systemic inflammation and IR, though other organs, such as skeletal muscle and liver, have also been implicated.4 Adipose tissue is a highly vascularized organ where every adipocyte is connected to at least one capillary.5 To maintain normal adipose tissue function, the proper signaling between adipocytes and endothelial cells (ECs) from the surrounding vasculature is important.6 There is a growing body of evidence suggesting that EC dysfunction contributes to the pathogenesis of atherosclerosis, obesity, and T2DM.7,8 Therefore, it is of key interest to further study the role of the crosstalk between adipose tissue ECs and adipocytes in obesity-associated IR and to identify potential therapeutic targets for novel interventions. Recently, several reports suggested that microRNAs (miRs) are important mediators of the development of inflammation and IR in obese adipose tissue.9 Subsequently, numerous studies explored targeting specific miRs in diabetic complications to mitigate the pathological sequela of T2DM.9 Given these points, using miRs to modulate adipocyte–EC axis in adipose tissue may offer new tools to combat the growing epidemic of obesity and its associated comorbidities. Article, see p 810 Over the past 2 decades, several studies elucidated the underlying molecular mechanisms linking inflammation to obesity-associated IR. Hotamisligil et al10 was the first to demonstrate …
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- 2016
32. Iron and Sex Cross Paths in the Heart
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Hossein Ardehali, Jason S. Shapiro, and Hsiang-Chun Chang
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Gerontology ,Cardiomyopathy ,Iron ,17‐β‐estradiol ,030204 cardiovascular system & hematology ,Pathophysiology ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,oxidative stress ,sex ,iron overload ,Cause of death ,Original Research ,Heart Failure ,business.industry ,Myocardium ,hemojuvelin ,Heart ,3. Good health ,ovariectomy ,myocardial fibrosis ,Cardiology and Cardiovascular Medicine ,business ,Oxidant Stress ,030217 neurology & neurosurgery ,Demography - Abstract
Background Sex‐related differences in cardiac function and iron metabolism exist in humans and experimental animals. Male patients and preclinical animal models are more susceptible to cardiomyopathies and heart failure. However, whether similar differences are seen in iron‐overload cardiomyopathy is poorly understood. Methods and Results Male and female wild‐type and hemojuvelin‐null mice were injected and fed with a high‐iron diet, respectively, to develop secondary iron overload and genetic hemochromatosis. Female mice were completely protected from iron‐overload cardiomyopathy, whereas iron overload resulted in marked diastolic dysfunction in male iron‐overloaded mice based on echocardiographic and invasive pressure‐volume analyses. Female mice demonstrated a marked suppression of iron‐mediated oxidative stress and a lack of myocardial fibrosis despite an equivalent degree of myocardial iron deposition. Ovariectomized female mice with iron overload exhibited essential pathophysiological features of iron‐overload cardiomyopathy showing distinct diastolic and systolic dysfunction, severe myocardial fibrosis, increased myocardial oxidative stress, and increased expression of cardiac disease markers. Ovariectomy prevented iron‐induced upregulation of ferritin, decreased myocardial SERCA2a levels, and increased NCX1 levels. 17β‐Estradiol therapy rescued the iron‐overload cardiomyopathy in male wild‐type mice. The responses in wild‐type and hemojuvelin‐null female mice were remarkably similar, highlighting a conserved mechanism of sex‐dependent protection from iron‐overload‐mediated cardiac injury. Conclusions Male and female mice respond differently to iron‐overload‐mediated effects on heart structure and function, and females are markedly protected from iron‐overload cardiomyopathy. Ovariectomy in female mice exacerbated iron‐induced myocardial injury and precipitated severe cardiac dysfunction during iron‐overload conditions, whereas 17β‐estradiol therapy was protective in male iron‐overloaded mice.
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- 2017
33. Getting to the 'Heart' of Cardiac Disease by Decreasing Mitochondrial Iron
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Jason S. Shapiro, Hsiang-Chun Chang, and Hossein Ardehali
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0301 basic medicine ,medicine.medical_specialty ,Iron Overload ,Heart Diseases ,Physiology ,Anemia ,Iron ,Myocardial Reperfusion Injury ,Disease ,030204 cardiovascular system & hematology ,Biology ,Mitochondrion ,Mitochondria, Heart ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Vitamin B12 ,Anemia, Iron-Deficiency ,Heart ,Iron deficiency ,medicine.disease ,Surgery ,030104 developmental biology ,Mitochondrial respiratory chain ,Heart failure ,Hemoglobin ,Cardiology and Cardiovascular Medicine - Abstract
Iron chelation rather than supplementation would be beneficial to patients with heart diseases. More effort should be devoted to the development of iron chelators that could target mitochondrial iron. Iron is an essential trace mineral for normal mammalian physiology. It is incorporated into iron/sulfur (Fe/S) clusters that serve as important cofactors for many enzymes, including the mitochondrial respiratory chain, and it gives blood and muscle their signature red color through its presence in heme.1 Because of its involvement in many important cellular processes, dysregulation of iron often causes disease. There are 2 broad categories of diseases associated with iron dysregulation—iron overload and iron deficiency. Each category can be further subdivided based on whether the changes in iron occur at the cellular or at the systemic level. Iron is critical for developmental processes, and studies have linked severe systemic iron deficiency to impaired brain development in children.2 However, most of these studies were conducted in developing countries where iron deficiency tends to be more severe. In developed countries, the major disorder associated with iron deficiency is anemia. Although systemic iron deficiency and anemia may have been used interchangeably, these 2 terms refer to different conditions. Systemic iron deficiency refers to low amounts of iron in circulation because of limited iron absorption or excess iron loss. Anemia is defined as low hemoglobin content within red blood cells and can be caused by low systemic iron, mutations in hemoglobin genes, vitamin B12 deficiency, or underlying chronic diseases. Limited oxygen-carrying capacity secondary to anemia can cause fatigue; however, it generally does not cause mortality or major damage to vital organs. Except for high-output heart failure (HF) associated with severe anemia, iron deficiency and anemia are not associated with any other major cardiac disorders. Cellular iron deficiency is a rare phenomenon, and except …
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- 2017
34. Heme Levels Are Increased in Human Failing Hearts
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Arineh Khechaduri, Hsiang-Chun Chang, Hossein Ardehali, and Marina Bayeva
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HMOX1 ,Blotting, Western ,Apoptosis ,Heme ,030204 cardiovascular system & hematology ,Mitochondrion ,Real-Time Polymerase Chain Reaction ,medicine.disease_cause ,Article ,Mitochondria, Heart ,03 medical and health sciences ,chemistry.chemical_compound ,iron ,Cytosol ,0302 clinical medicine ,Downregulation and upregulation ,Humans ,Medicine ,Myocytes, Cardiac ,Cells, Cultured ,Heart metabolism ,030304 developmental biology ,Heart Failure ,chemistry.chemical_classification ,0303 health sciences ,Reactive oxygen species ,business.industry ,ALAS2 ,Cell biology ,mitochondria ,Gene Expression Regulation ,chemistry ,Immunology ,RNA ,Reactive Oxygen Species ,business ,Cardiology and Cardiovascular Medicine ,Oxidative stress ,5-Aminolevulinate Synthetase - Abstract
Objectives The goal of this study was to characterize the regulation of heme and non-heme iron in human failing hearts. Background Iron is an essential molecule for cellular physiology, but in excess it facilitates oxidative stress. Mitochondria are the key regulators of iron homeostasis through heme and iron-sulfur cluster synthesis. Because mitochondrial function is depressed in failing hearts and iron accumulation can lead to oxidative stress, we hypothesized that iron regulation may also be impaired in heart failure (HF). Methods We measured mitochondrial and cytosolic heme and non-heme iron levels in failing human hearts retrieved during cardiac transplantation surgery. In addition, we examined the expression of genes regulating cellular iron homeostasis, the heme biosynthetic pathway, and micro-RNAs that may potentially target iron regulatory networks. Results Although cytosolic non-heme iron levels were reduced in HF, mitochondrial iron content was maintained. Moreover, we observed a significant increase in heme levels in failing hearts, with corresponding feedback inhibition of the heme synthetic enzymes and no change in heme degradation. The rate-limiting enzyme in heme synthesis, delta-aminolevulinic acid synthase 2 (ALAS2), was significantly upregulated in HF. Overexpression of ALAS2 in H9c2 cardiac myoblasts resulted in increased heme levels, and hypoxia and erythropoietin treatment increased heme production through upregulation of ALAS2. Finally, increased heme levels in cardiac myoblasts were associated with excess production of reactive oxygen species and cell death, suggesting a maladaptive role for increased heme in HF. Conclusions Despite global mitochondrial dysfunction, heme levels are maintained above baseline in human failing hearts.
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- 2013
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35. mTOR Regulates Cellular Iron Homeostasis through Tristetraprolin
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Hossein Ardehali, Hsiang-Chun Chang, Sergi Puig, Marina Bayeva, Perry J. Blackshear, Sonika Patial, and Arineh Khechaduri
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Saccharomyces cerevisiae Proteins ,Physiology ,Iron ,Tristetraprolin ,Gene Expression ,Transferrin receptor ,Saccharomyces cerevisiae ,Biology ,Article ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,RNA interference ,Receptors, Transferrin ,Tuberous Sclerosis Complex 2 Protein ,Animals ,RNA, Messenger ,RNA, Small Interfering ,Transcription factor ,Molecular Biology ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Sirolimus ,0303 health sciences ,TOR Serine-Threonine Kinases ,Tumor Suppressor Proteins ,Cell Biology ,DNA-Binding Proteins ,Biochemistry ,030220 oncology & carcinogenesis ,RNA Interference ,Flux (metabolism) ,Transcription Factors - Abstract
SummaryIron is an essential cofactor with unique redox properties. Iron-regulatory proteins 1 and 2 (IRP1/2) have been established as important regulators of cellular iron homeostasis, but little is known about the role of other pathways in this process. Here we report that the mammalian target of rapamycin (mTOR) regulates iron homeostasis by modulating transferrin receptor 1 (TfR1) stability and altering cellular iron flux. Mechanistic studies identify tristetraprolin (TTP), a protein involved in anti-inflammatory response, as the downstream target of mTOR that binds to and enhances degradation of TfR1 mRNA. We also show that TTP is strongly induced by iron chelation, promotes downregulation of iron-requiring genes in both mammalian and yeast cells, and modulates survival in low-iron states. Taken together, our data uncover a link between metabolic, inflammatory, and iron-regulatory pathways, and point toward the existence of a yeast-like TTP-mediated iron conservation program in mammals.
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- 2012
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36. Correction: Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice
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Yuzhi Jia, Hsiang-Chun Chang, Matthew J. Schipma, Jing Liu, Varsha Shete, Ning Liu, Tatsuya Sato, Edward B. Thorp, Philip M. Barger, Yi-Jun Zhu, Navin Viswakarma, Yashpal S. Kanwar, Hossein Ardehali, Bayar Thimmapaya, and Janardan K. Reddy
- Subjects
Cardiomyopathy, Dilated ,Calcium Channels, L-Type ,Peroxisome Proliferator-Activated Receptors ,lcsh:Medicine ,Apoptosis ,Gestational Age ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,03 medical and health sciences ,Mediator Complex Subunit 1 ,Mice ,0302 clinical medicine ,Pregnancy ,Animals ,Myocytes, Cardiac ,Calcium Signaling ,lcsh:Science ,Heart Failure ,Mice, Knockout ,Multidisciplinary ,Gene Expression Profiling ,lcsh:R ,Correction ,Ryanodine Receptor Calcium Release Channel ,Cadherins ,Cyclic Nucleotide Phosphodiesterases, Type 1 ,Embryo, Mammalian ,Myocardial Contraction ,Mitochondria ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,lcsh:Q ,Female ,Genes, Lethal ,Energy Metabolism ,030217 neurology & neurosurgery ,Gene Deletion - Abstract
Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with developmental impairment of multiple organs including heart. Here we show that cardiomyocyte-specific deletion of Med1 in mice (csMed1-/-) during late gestational and early postnatal development by intercrossing Med1fl/fl mice to α-MyHC-Cre transgenic mice results in lethality within 10 days after weaning due to dilated cardiomyopathy-related ventricular dilation and heart failure. The csMed1-/- mouse heart manifests mitochondrial damage, increased apoptosis and interstitial fibrosis. Global gene expression analysis revealed that loss of Med1 in heart down-regulates more than 200 genes including Acadm, Cacna1s, Atp2a2, Ryr2, Pde1c, Pln, PGC1α, and PGC1β that are critical for calcium signaling, cardiac muscle contraction, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and peroxisome proliferator-activated receptor regulated energy metabolism. Many genes essential for oxidative phosphorylation and proper mitochondrial function such as genes coding for the succinate dehydrogenase subunits of the mitochondrial complex II are also down-regulated in csMed1-/- heart contributing to myocardial injury. Data also showed up-regulation of about 180 genes including Tgfb2, Ace, Atf3, Ctgf, Angpt14, Col9a2, Wisp2, Nppa, Nppb, and Actn1 that are linked to cardiac muscle contraction, cardiac hypertrophy, cardiac fibrosis and myocardial injury. Furthermore, we demonstrate that cardiac specific deletion of Med1 in adult mice using tamoxifen-inducible Cre approach (TmcsMed1-/-), results in rapid development of cardiomyopathy and death within 4 weeks. We found that the key findings of the csMed1-/- studies described above are highly reproducible in TmcsMed1-/- mouse heart. Collectively, these observations suggest that Med1 plays a critical role in the maintenance of heart function impacting on multiple metabolic, compensatory and reparative pathways with a likely therapeutic potential in the management of heart failure.
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- 2016
37. Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling
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Hossein Ardehali, Amy K. Rines, Paul T. Schumacker, Arineh Khechaduri, Chunlei Chen, Tenley A. Rawlings, Hidemichi Kouzu, Michael A. Burke, Xinghang Jiang, Tatsuya Sato, E. Dale Abel, Rongxue Wu, Jason S. Shapiro, Meng Shang, Hsiang-Chun Chang, and Gary D. Lopaschuk
- Subjects
0301 basic medicine ,Male ,Science ,General Physics and Astronomy ,Down-Regulation ,Apoptosis ,Cell Cycle Proteins ,Myocardial Reperfusion Injury ,Mitochondrion ,Protein Serine-Threonine Kinases ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cell Line ,03 medical and health sciences ,Mice ,Dogs ,Uncoupling protein ,Animals ,Humans ,Uncoupling Protein 3 ,PPAR alpha ,Protein kinase A ,UCP3 ,Mice, Knockout ,Multidisciplinary ,Chemistry ,Kinase ,Myocardium ,AMPK ,Isolated Heart Preparation ,General Chemistry ,Corrigenda ,Cell biology ,Mitochondria ,Mice, Inbred C57BL ,Repressor Proteins ,Disease Models, Animal ,030104 developmental biology ,HEK293 Cells ,TRIB3 ,Gene Knockdown Techniques ,Knockout mouse ,Female - Abstract
Ischaemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in tissue death. Here, we demonstrate that the AMP-activated protein kinase (AMPK)-related protein Snf1-related kinase (SNRK) decreases cardiac metabolic substrate usage and mitochondrial uncoupling, and protects against ischaemia/reperfusion. Hearts from transgenic mice overexpressing SNRK have decreased glucose and palmitate metabolism and oxygen consumption, but maintained power and function. They also exhibit decreased uncoupling protein 3 (UCP3) and mitochondrial uncoupling. Conversely, Snrk knockout mouse hearts have increased glucose and palmitate oxidation and UCP3. SNRK knockdown in cardiac cells decreases mitochondrial efficiency, which is abolished with UCP3 knockdown. We show that Tribbles homologue 3 (Trib3) binds to SNRK, and downregulates UCP3 through PPARα. Finally, SNRK is increased in cardiomyopathy patients, and SNRK reduces infarct size after ischaemia/reperfusion. SNRK also decreases cardiac cell death in a UCP3-dependent manner. Our results suggest that SNRK improves cardiac mitochondrial efficiency and ischaemic protection., The Snf1-related kinase (SNRK) is widely expressed and yet its function is poorly understood. Here the authors show that SNRK regulates mitochondrial coupling via the Trib3-PPARα-UCP3 pathway and that cardiac overexpression of SNRK decreases metabolic substrate usage and oxygen consumption but maintains cardiac function and energy in mice.
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- 2016
38. Abstract 15796: Increased Cardiac Heme Levels Through Cardiac Overexpression of Delta-aminolevulinic Acid Synthase 2 (ALAS2) Lead to Exacerbated Ischemic Injury
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Konrad T Sawicki, Meng Shang, Rongxue Wu, Hsiang-Chun Chang, Arineh Khechaduri, Tatsuya Sato, Christine Kamide, Ting Liu, Sathyamangla N Prasad, and Hossein Ardehali
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Heme is an essential iron-containing molecule for cardiovascular physiology, but in excess it may increase oxidative stress. Failing human hearts have increased heme levels, with upregulation of the rate-limiting enzyme in heme synthesis, δ-aminolevulinic acid synthase 2 (ALAS2), which is normally not expressed in cardiomyocytes. Hypothesis: We hypothesized that increased heme accumulation (through cardiac overexpression of ALAS2) leads to increased oxidative stress and cell death in the heart. Results: We first showed that ALAS2 and heme levels are increased in the hearts of mice subjected to coronary ligation. To determine the causative role of increased heme in the development of heart failure, we generated transgenic mice with cardiac-specific overexpression of ALAS2. While ALAS2 transgenic mice have normal cardiac function at baseline, their hearts display increased heme content, higher oxidative stress, exacerbated cell death, and worsened cardiac function after coronary ligation compared to non-transgenic littermates. We confirmed in cultured cardiomyoblasts that the increased oxidative stress and cell death by ALAS2 overexpression is mediated by increased heme accumulation. Furthermore, knockdown of ALAS2 in cultured cardiomyoblasts exposed to hypoxia reversed the increases in heme content and cell death. Administration of the mitochondrial antioxidant MitoTempo to ALAS2-overexpressing cardiomyoblasts normalized the elevated oxidative stress and cell death levels to baseline, indicating that the effects of increased ALAS2 and heme are through elevated mitochondrial oxidative stress. The clinical relevance of these findings was supported by the finding of increased ALAS2 induction and heme accumulation in failing human hearts from patients with ischemic cardiomyopathy compared to non-ischemic cardiomyopathy. Conclusions: Heme accumulation is detrimental to cardiac function under ischemic conditions, and reducing heme in the heart may be a novel approach for protection against the development of heart failure.
- Published
- 2015
39. Abstract 15100: A Decrease in Mitochondrial, but Not Cytosolic, Iron Protects Against Cardiac Ischemia-Reperfusion Damage Through a Reduction in ROS
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Hsiang-Chun Chang, Rongxue Wu, Meng Shang, and Hossein Ardehali
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Iron can catalyze the formation of reactive oxygen species (ROS) and promote tissue damage. While some studies suggested benefits with iron chelation therapy in ischemic heart disease (IHD), several others failed to show any benefits. Mitochondria are a major site of iron utilization and ROS production, and mitochondrial iron accumulation has been associated with increased oxidative stress. We therefore hypothesized that mitochondrial iron plays a causative role in ischemia/reperfusion (I/R) damage, and a decrease in mitochondrial iron (as opposed to cytoplasmic iron) would be sufficient to protect against I/R injury. Results: We observed an increase in cardiac mitochondrial iron in mice after I/R injury. Using two iron chelators with distinct mitochondrial permeability, i.e., 2,2’-bipyridyl (BPD, a mitochondria-accessible iron chelator) and deferoxamine (DFO, an iron chelator that does not modulate mitochondrial iron), we demonstrated that mice pretreated with BPD but not DFO were protected against I/R injury. Similar results were obtained in vitro . Since these two iron chelators also modulate iron in other subcellular compartments, we used transgenic (TG) mice with cardiomyocyte-specific overexpression of the mitochondrial iron export protein ATP-binding cassette (ABC)-B8 to confirm that modulation of mitochondrial iron alone is sufficient to confer protection. ABCB8 TG mice had significantly lower mitochondrial iron (but normal cytosolic iron) in the heart compared to nontransgenic (NTG) littermates at baseline, but exhibited normal cardiac function. After I/R, ABCB8 TG mice displayed significantly less apoptosis and lower levels of markers of ROS and better preserved cardiac function than NTG littermates, suggesting that a reduction in mitochondrial iron protects against I/R injury, most likely through a reduction in ROS. Conclusions: Our findings demonstrate that selective reduction in mitochondrial iron is sufficient to protect against I/R injury. Thus, targeting mitochondrial iron with selective iron chelators may provide a novel approach for the treatment of IHD.
- Published
- 2015
40. Abstract 16240: Tristetraprolin (TTP) is a Novel Regulator of Branched-chain Amino Acid (BCAA) Catabolism in the Heart
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Sumeyye Yar, Hsiang-Chun Chang, Meng Shang, and Hossein Ardehali
- Subjects
hemic and lymphatic diseases ,Physiology (medical) ,heterocyclic compounds ,respiratory system ,Cardiology and Cardiovascular Medicine ,therapeutics - Abstract
Introduction: Heart failure (HF) is associated with the accumulation of branched-chain amino acids (BCAAs) in heart and plasma. Besides, BCAAs are essential for normal cell growth and function. Therefore, tight regulation of BCAA metabolism is crucial to maintain normal cellular homeostasis. Tristetraprolin (TTP), an mRNA binding protein that promotes the degradation of its targets and regulates a number of biological processes including cellular metabolism. In in silico analyses, we identified the E2 subunit of branched-chain α-ketoacid dehydrogenase complex (BCKDC), the rate-limiting enzyme complex in BCAA catabolism, as a potential target of TTP. Here we assess the hypothesis that TTP plays a regulatory role in BCAA catabolism through regulating BCKDC-E2 in the heart. We also investigate TTP’s contribution in the pathogenesis of HF by modulating BCAA catabolism. Results: We observed a significant increase in TTP levels in cardiac tissue of human HF and mouse myocardial infarct induced HF samples. We also showed that deletion of TTP significantly decreases BCAA levels in vitro. As BCAA accumulation in the heart is associated with the pathogenesis of HF, we investigated whether TTP can regulate cardiac BCAA catabolism. Computational analysis of mRNAs of enzymes, which are involved in BCAA catabolism, revealed highly conserved TTP binding sites in BCKDC-E2 mRNA, suggesting that it is a potential target of TTP. BCKDC-E2 mRNA levels were significantly higher in the heart of TTP knock-out mice and TTP siRNA treated cardiomyocytes. Additionally, the mRNA stability of BCKDC-E2 was higher in cardiomyocytes with TTP downregulation, further confirming that TTP regulates the stability of this mRNA. Moreover, RNA co-immunoprecipitation studies demonstrated that TTP physically interacts with the BCKDC-E2 mRNA. Finally, we showed that BCKDC-E2 mRNA levels were significantly decreased in human HF samples. Conclusion: Our data indicate that TTP levels are increased in HF samples and TTP regulates BCAA catabolism in the heart by binding to and degrading BCKDC-E2 mRNA. These findings suggest that alterations in TTP expression may play a role in the development of HF based on its effect upon BCKDC-E2 and BCAA catabolism.
- Published
- 2015
41. Dual Inhibition of Both the Epidermal Growth Factor Receptor and erbB2 Effectively Inhibits the Promotion of Skin Tumors during Two-Stage Carcinogenesis
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Kaoru Kiguchi, John DiGiovanni, Lynnsie Ruffino, Hsiang-Chun Chang, Mohammad Rumi, Tricia Moore, Devon Treece, Kevin Connolly, and Takuya Kitamura
- Subjects
Cancer Research ,medicine.medical_specialty ,integumentary system ,biology ,Epidermis (botany) ,medicine.disease_cause ,Inhibitory postsynaptic potential ,Two stage carcinogenesis ,Receptor tyrosine kinase ,Basal (phylogenetics) ,Endocrinology ,Oncology ,Internal medicine ,medicine ,biology.protein ,Cancer research ,Tumor promotion ,Epidermal growth factor receptor ,skin and connective tissue diseases ,Carcinogenesis ,neoplasms - Abstract
The erbB family of receptor tyrosine kinases are known to play important roles in normal epithelial development and epithelial neoplasia. Considerable evidence also suggests that signaling through the epidermal growth factor receptor (EGFR) plays an important role in multistage skin carcinogenesis in mice; however, less is known about the role of erbB2. In this study, to further examine the role of both erbB2 and EGFR in epithelial carcinogenesis, we examined the effect of a dual erbB2/EGFR tyrosine kinase inhibitor, GW2974, given in the diet on skin tumor promotion during two-stage carcinogenesis in wild-type and BK5.erbB2 mice. In BK5.erbB2 mice, erbB2 is overexpressed in the basal layer of epidermis and leads to heightened sensitivity to skin tumor development. GW2974 effectively inhibited skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in wild-type and BK5.erbB2 mice, although a more marked effect was seen in BK5.erbB2 mice. In addition, this inhibitory effect was reversible when GW2974 treatment was withdrawn. GW2974 inhibited 12-O-tetradecanoylphorbol-13-acetate–induced epidermal hyperproliferation, which correlated with reduced activation of both the EGFR and erbB2. These results support the hypothesis that both the EGFR and erbB2 play an important role in the development of skin tumors during two-stage skin carcinogenesis, especially during the tumor promotion stage. Furthermore, the marked sensitivity of BK5.erbB2 mice to the inhibitory effects of GW2974 during tumor promotion suggest greater efficacy for this compound when erbB2 is overexpressed or amplified as an early event in the carcinogenic process. Cancer Prev Res; 3(8); 940–52. ©2010 AACR.
- Published
- 2010
42. Abstract 115: A Decrease in Mitochondrial, but Not Cytosolic, Iron Protects Against Cardiac Ischemia-reperfusion Damage Through a Reduction in Ros
- Author
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Hsiang-Chun Chang, Rongxue Wu, and Hossein Ardehali
- Subjects
Physiology ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Iron is essential for the activity of several cellular proteins, but excess free iron can cause cellular damage through production of reactive oxygen species (ROS). Iron accumulation in mitochondria, the major site of cellular iron homeostasis, leads to cardiomyopathy. However, it is not known whether a reduction in baseline mitochondrial iron (as opposed to iron in other cellular compartments) can protect against ischemia-reperfusion (I/R) injury in the heart. We hypothesized that since mitochondria are the major site of iron homeostasis and that mitochondrial iron can lead to oxidative damage, a reduction in mitochondrial iron at baseline would be sufficient to protect against I/R injury. Results: Transgenic (TG) mice with cardiomyocyte-specific overexpression of the mitochondrial iron export protein ATP-binding cassette (ABC)-B8 had significantly lower mitochondrial iron in the heart than nontransgenic (NTG) littermates at baseline, but their cardiac function and the expression of key antioxidant systems were similar to NTG littermates. In response to I/R, TG mice displayed significantly less apoptosis and lipid peroxidation products and better preserved cardiac function than NTG littermates, suggesting that a reduction in mitochondrial iron protects against I/R injury. To confirm these results, we next took a pharmacological approach to assess the effects of a reduction in mitochondrial vs cytosolic iron on the response to I/R using 2,2’-bipyridyl (BPD, a mitochondria-accessible iron chelator) and deferoxamine (DFO, an iron chelator that can only reduce cytosolic iron). Mice pretreated with BPD but not DFO are protected against I/R injury. In addition, BPD but not DFO treatment in rat cardiomyoblast H9C2 cells significantly lowered chelatable mitochondrial iron and protected against H2O2 induced cell death. These results suggest that a reduction in baseline mitochondrial, but not cytosolic, iron is sufficient to protect against I/R injury. Conclusions: Our findings demonstrate that selective reduction in mitochondrial iron is protective in I/R injury. Thus, targeting mitochondrial iron with selective iron chelators may provide a novel approach for treatment of ischemic heart disease.
- Published
- 2015
43. Increased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury
- Author
-
Konrad T Sawicki, Christine Kamide, Arineh Khechaduri, Sathyamangla V. Naga Prasad, Tatsuya Sato, Rongxue Wu, Hossein Ardehali, Meng Shang, Ting Liu, and Hsiang-Chun Chang
- Subjects
Cardiac function curve ,Programmed cell death ,medicine.medical_specialty ,Myocardial Infarction ,Mice, Transgenic ,Heme ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Transfection ,Antioxidants ,Mitochondria, Heart ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,iron ,Internal medicine ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,Cells, Cultured ,030304 developmental biology ,Original Research ,Heart Failure ,0303 health sciences ,Ischemic cardiomyopathy ,Cell Death ,business.industry ,apoptosis ,medicine.disease ,ALAS2 ,3. Good health ,Up-Regulation ,Disease Models, Animal ,Oxidative Stress ,Endocrinology ,chemistry ,Apoptosis ,Heart failure ,Enzyme Induction ,RNA Interference ,Cardiology and Cardiovascular Medicine ,business ,metabolism ,Oxidative stress ,5-Aminolevulinate Synthetase ,Signal Transduction - Abstract
Background Heme is an essential iron‐containing molecule for cardiovascular physiology, but in excess it may increase oxidative stress. Failing human hearts have increased heme levels, with upregulation of the rate‐limiting enzyme in heme synthesis, δ‐aminolevulinic acid synthase 2 ( ALAS 2), which is normally not expressed in cardiomyocytes. We hypothesized that increased heme accumulation (through cardiac overexpression of ALAS 2) leads to increased oxidative stress and cell death in the heart. Methods and Results We first showed that ALAS 2 and heme levels are increased in the hearts of mice subjected to coronary ligation. To determine the causative role of increased heme in the development of heart failure, we generated transgenic mice with cardiac‐specific overexpression of ALAS 2. While ALAS 2 transgenic mice have normal cardiac function at baseline, their hearts display increased heme content, higher oxidative stress, exacerbated cell death, and worsened cardiac function after coronary ligation compared to nontransgenic littermates. We confirmed in cultured cardiomyoblasts that the increased oxidative stress and cell death observed with ALAS 2 overexpression is mediated by increased heme accumulation. Furthermore, knockdown of ALAS 2 in cultured cardiomyoblasts exposed to hypoxia reversed the increases in heme content and cell death. Administration of the mitochondrial antioxidant MitoTempo to ALAS 2‐overexpressing cardiomyoblasts normalized the elevated oxidative stress and cell death levels to baseline, indicating that the effects of increased ALAS 2 and heme are through elevated mitochondrial oxidative stress. The clinical relevance of these findings was supported by the finding of increased ALAS 2 induction and heme accumulation in failing human hearts from patients with ischemic cardiomyopathy compared to nonischemic cardiomyopathy. Conclusions Heme accumulation is detrimental to cardiac function under ischemic conditions, and reducing heme in the heart may be a novel approach for protection against the development of heart failure.
- Published
- 2015
44. Role of heme in cardiovascular physiology and disease
- Author
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Konrad T Sawicki, Hsiang-Chun Chang, and Hossein Ardehali
- Subjects
Pathology ,medicine.medical_specialty ,Antioxidant ,medicine.medical_treatment ,Disease ,Heme ,heart ,Mitochondrion ,7. Clean energy ,Cardiovascular Physiological Phenomena ,chemistry.chemical_compound ,iron ,cardiovascular disease ,Medicine ,Humans ,Contemporary Reviews ,business.industry ,Role ,3. Good health ,Cardiovascular physiology ,Anemia, Sideroblastic ,mitochondria ,Biochemistry ,chemistry ,Cardiovascular Diseases ,cardiovascular physiology ,Signal transduction ,Cardiology and Cardiovascular Medicine ,business - Abstract
Heme is an essential molecule for living aerobic organisms and is involved in a remarkable array of diverse biological processes. In the cardiovascular system, heme plays a major role in gas exchange, mitochondrial energy production, antioxidant defense, and signal transduction. Although heme, as
- Published
- 2015
45. Abstract 15414: Ablation of Aryl Hydrocarbon Nuclear Translocator (ARNT) in the Heart Leads to Diabetic Cardiomyopathy Phenotype Through PPARα Activity
- Author
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Rongxue Wu, Hsiang Chun Chang, Minh Tran, Kusum Chawla, Arineh Khechaduri, Xiaomeng Chai, Mohsen Ghanefar, Marina Bayeva, Cory Wagg, Frank Gonzalez, Gary Lopaschuk, and Hossein Ardehali
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Background: Metabolic changes decrease cardiac efficiency and energetics in diabetes. Impaired hypoxia inducible factor (HIF) signaling may contribute to cardiac metabolic abnormalities. ARNT, also known as HIF1β, is a transcription factor that regulates several cellular processes by dimerizing with certain proteins, including HIF-1α or -2α, and its function in the heart is unknown. We hypothesized that cardiac deletion of ARNT leads to metabolic derangement and cardiac dysfunction. Methods and Results: Cardiac-specific ARNT knockout (csARNT-KO) mice were generated by our lab as previously described. ARNT deletion in the heart resulted in dilated cardiomyopathy and significant lipid accumulation, which was determined by electron microscopy, oil-red staining and triglyceride level quantification. We found that loss of ARNT in the heart increased PPARα activity, as confirmed by 2-fold increase in fatty acid oxidation (FAO) in ex-vivo csARNT+/- working hearts, increased PPARα protein content and increased PPARα target gene expression.To study the mechanism by which ARNT regulates PPARα, luciferase reporter assays revealed that ARNT knockdown resulted in increased PPARα promoter activity and deletion of the second hypoxia response element (HRE) upstream of the initiation site removed the inhibitory effect of ARNT on the PPARα promoter, suggesting that this site is likely involved in the regulation of the gene. ARNT binding to this sequence was confirmed by chromatin immunoprecipitation analysis. Moreover, a reduction in HIF-2α, but not HIF-1α or AHR, also significantly increased the levels of PPARα. These results suggest that the effects of ARNT deletion on PPARα are, at least partially, through its association with HIF-2α and through the binding of this complex to the second HRE upstream of the PPARα initiation site. Finally, mice with double deletion of ARNT and PPARα demonstrated rescue of the cardiac dysfunction phenotype, improved survival, and complete reversal of FA accumulation. Conclusion: Reduction in ARNT levels leads to cardiomyopathy by increasing lipid accumulation through a PPARα pathway. Thus, ARNT is a critical regulator of fatty acid metabolism in the heart, and a potential target for the treatment of diabetic cardiomyopathy.
- Published
- 2014
46. Abstract 12282: A Decrease in Mitochondrial, but Not Cytosolic, Iron Protects Against Cardiac Ischemia-Reperfusion Damage Through a Reduction in ROS
- Author
-
Hossein Ardehali, Rongxue Wu, and Hsiang-Chun Chang
- Subjects
chemistry.chemical_classification ,Programmed cell death ,Reactive oxygen species ,Antioxidant ,business.industry ,medicine.medical_treatment ,Pharmacology ,Mitochondrion ,Lipid peroxidation ,Deferoxamine ,Cytosol ,chemistry.chemical_compound ,Biochemistry ,chemistry ,Apoptosis ,Physiology (medical) ,medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Introduction: Iron is essential for the activity of several cellular proteins, but excess free iron can cause cellular damage through production of reactive oxygen species (ROS). Iron accumulation in mitochondria, the major site of cellular iron homeostasis, leads to cardiomyopathy. However, it is not known whether a reduction in baseline mitochondrial (as opposed to cytosolic) iron can protect against ischemia-reperfusion (I/R) injury in the heart. We hypothesized that since mitochondria are the major site of iron homeostasis and that mitochondrial iron can lead to oxidative damage, a reduction in mitochondrial iron at baseline would be sufficient to protect against I/R injury. Results: Transgenic (TG) mice with cardiomyocyte-specific overexpression of the mitochondrial iron export protein ATP-binding cassette (ABC)-B8 had significantly lower mitochondrial iron in the heart than nontransgenic (NTG) littermates at baseline, but their cardiac function and the expression of key antioxidant systems were similar to NTG littermates. In response to I/R, TG mice displayed significantly less apoptosis and lipid peroxidation products and better preserved cardiac function than NTG littermates, suggesting that a reduction in mitochondrial iron protects against I/R injury. To confirm these results, we next took a pharmacological approach to assess the effects of a reduction in mitochondrial vs cytosolic iron on the response to I/R using 2,2’-bipyridyl (BPD, a mitochondria-accessible iron chelator) and deferoxamine (DFO, an iron chelator that can only reduce cytosolic iron). Treating rat cardiomyoblast H9C2 cells with BPD but not DFO significantly lowered chelatable mitochondrial iron and protected against H 2 O 2 induced cell death, and pretreatment with BPD but not DFO protected mice against I/R injury and reduced ROS production, suggesting that a reduction in baseline mitochondrial, but not cytosolic, iron is sufficient to protect against I/R injury. Conclusions: Our findings demonstrate that selective reduction in mitochondrial iron is protective in I/R injury. Thus, targeting mitochondrial iron with selective iron chelators may provide a novel approach for treatment of ischemic heart disease.
- Published
- 2014
47. Correction: Corrigendum: Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling
- Author
-
Gary D. Lopaschuk, Hidemichi Kouzu, E. Dale Abel, Hossein Ardehali, Arineh Khechaduri, Eltyeb Abdelwahid, Chunlei Chen, Amy K. Rines, Hsiang-Chun Chang, Tenley A. Rawlings, Xinghang Jiang, Meng Shang, Michael A. Burke, Jason S. Shapiro, Rongxue Wu, Tatsuya Sato, and Paul T. Schumacker
- Subjects
Multidisciplinary ,business.industry ,Kinase ,Published Erratum ,Science ,MEDLINE ,General Physics and Astronomy ,Medicine ,General Chemistry ,Computational biology ,business ,General Biochemistry, Genetics and Molecular Biology - Abstract
Nature Communications 8: Article number: 14095 (2017); Published: 24 January 2017; Updated: 30 August 2017. The authors inadvertently omitted Eltyeb Abdelwahid, who contributed to the generation of animal models and their initial evaluation, from the author list. This has now been corrected in both the PDF and HTML versions of the Article.
- Published
- 2017
48. Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy
- Author
-
Cory S. Wagg, Kusum Chawla, Xiaomeng Chai, Hsiang-Chun Chang, Hossein Ardehali, Rongxue Wu, Minh Tran, Xinghang Jiang, Marina Bayeva, Mohsen Ghanefar, Frank J. Gonzalez, Arineh Khechaduri, and Gary D. Lopaschuk
- Subjects
medicine.medical_specialty ,Aryl hydrocarbon receptor nuclear translocator ,Transcription, Genetic ,Diabetic Cardiomyopathies ,Cardiomyopathy ,Peroxisome proliferator-activated receptor ,Mice, Obese ,Biology ,Rats, Sprague-Dawley ,Gene Knockout Techniques ,Lipid droplet ,Internal medicine ,Diabetic cardiomyopathy ,medicine ,Animals ,Humans ,PPAR alpha ,Triglycerides ,Regulation of gene expression ,chemistry.chemical_classification ,Mice, Knockout ,Ventricular Remodeling ,Myocardium ,Aryl Hydrocarbon Receptor Nuclear Translocator ,Fatty Acids ,Lipid metabolism ,General Medicine ,medicine.disease ,Lipid Metabolism ,Endocrinology ,HEK293 Cells ,chemistry ,Lipotoxicity ,Gene Expression Regulation ,Oxidation-Reduction ,Research Article - Abstract
Patients with type 2 diabetes often present with cardiovascular complications; however, it is not clear how diabetes promotes cardiac dysfunction. In murine models, deletion of the gene encoding aryl hydrocarbon nuclear translocator (ARNT, also known as HIF1β) in the liver or pancreas leads to a diabetic phenotype; however, the role of ARNT in cardiac metabolism is unknown. Here, we determined that cardiac-specific deletion of Arnt in adult mice results in rapid development of cardiomyopathy (CM) that is characterized by accumulation of lipid droplets. Compared with hearts from ARNT-expressing mice, ex vivo analysis of ARNT-deficient hearts revealed a 2-fold increase in fatty acid (FA) oxidation as well as a substantial increase in the expression of PPARα and its target genes. Furthermore, deletion of both Arnt and Ppara preserved cardiac function, improved survival, and completely reversed the FA accumulation phenotype, indicating that PPARα mediates the detrimental effects of Arnt deletion in the heart. Finally, we determined that ARNT directly regulates Ppara expression by binding to its promoter and forming a complex with HIF2α. Together, these findings suggest that ARNT is a critical regulator of myocardial FA metabolism and that its deletion leads to CM and an increase in triglyceride accumulation through PPARα.
- Published
- 2014
49. When less is more: novel mechanisms of iron conservation
- Author
-
Marina Bayeva, Rongxue Wu, Hsiang-Chun Chang, and Hossein Ardehali
- Subjects
Iron-Regulatory Proteins ,Endocrinology, Diabetes and Metabolism ,Iron ,Energy metabolism ,Iron deficiency ,Computational biology ,Iron Deficiencies ,Biology ,medicine.disease ,Article ,Endocrinology ,Iron homeostasis ,Biochemistry ,Tristetraprolin ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Adaptation ,Iron acquisition - Abstract
Disorders of iron homeostasis are very common, yet the molecular mechanisms of iron regulation remain understudied. Over 20 years have passed since the first characterization of iron-regulatory proteins (IRP) as mediators of cellular iron-deficiency response in mammals through iron acquisition. However, little is known about other mechanisms necessary for adaptation to low-iron states. In this review, we present recent evidence that establishes the existence of a new iron-regulatory pathway aimed at iron conservation and optimization of iron use through suppression of nonessential iron-consuming processes. Moreover, we discuss the possible links between iron homeostasis and energy metabolism uncovered by studies of iron-deficiency response.
- Published
- 2013
50. Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice
- Author
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Yuzhi Jia, Yi Jun Zhu, Ning Liu, Matthew J. Schipma, Jing Liu, Varsha Shete, Tatsuya Sato, Hossein Ardehali, Bayar Thimmapaya, Philip M. Barger, Hsiang-Chun Chang, Yashpal S. Kanwar, Janardan K. Reddy, Edward B. Thorp, and Navin Viswakarma
- Subjects
0301 basic medicine ,Muscle Physiology ,Physiology ,Cardiac fibrosis ,Cardiomyopathy ,lcsh:Medicine ,Gene Expression ,Biochemistry ,Ryanodine receptor 2 ,MED1 ,Cell Signaling ,Medicine and Health Sciences ,Myocyte ,lcsh:Science ,Energy-Producing Organelles ,Multidisciplinary ,Heart ,Dilated cardiomyopathy ,Animal Models ,Mitochondria ,3. Good health ,Anatomy ,Cellular Structures and Organelles ,Cardiomyopathies ,Research Article ,Signal Transduction ,Muscle Contraction ,Genetically modified mouse ,medicine.medical_specialty ,Cardiology ,Mouse Models ,Bioenergetics ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,Internal medicine ,Genetics ,medicine ,Calcium Signaling ,lcsh:R ,Biology and Life Sciences ,Cell Biology ,medicine.disease ,Fibrosis ,030104 developmental biology ,Endocrinology ,Heart failure ,Cardiovascular Anatomy ,lcsh:Q ,Developmental Biology - Abstract
Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with developmental impairment of multiple organs including heart. Here we show that cardiomyocyte-specific deletion of Med1 in mice (csMed1-/-) during late gestational and early postnatal development by intercrossing Med1fl/fl mice to α-MyHC-Cre transgenic mice results in lethality within 10 days after weaning due to dilated cardiomyopathy-related ventricular dilation and heart failure. The csMed1-/- mouse heart manifests mitochondrial damage, increased apoptosis and interstitial fibrosis. Global gene expression analysis revealed that loss of Med1 in heart down-regulates more than 200 genes including Acadm, Cacna1s, Atp2a2, Ryr2, Pde1c, Pln, PGC1α, and PGC1β that are critical for calcium signaling, cardiac muscle contraction, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and peroxisome proliferator-activated receptor regulated energy metabolism. Many genes essential for oxidative phosphorylation and proper mitochondrial function such as genes coding for the succinate dehydrogenase subunits of the mitochondrial complex II are also down-regulated in csMed1-/- heart contributing to myocardial injury. Data also showed up-regulation of about 180 genes including Tgfb2, Ace, Atf3, Ctgf, Angpt14, Col9a2, Wisp2, Nppa, Nppb, and Actn1 that are linked to cardiac muscle contraction, cardiac hypertrophy, cardiac fibrosis and myocardial injury. Furthermore, we demonstrate that cardiac specific deletion of Med1 in adult mice using tamoxifen-inducible Cre approach (TmcsMed1-/-), results in rapid development of cardiomyopathy and death within 4 weeks. We found that the key findings of the csMed1-/- studies described above are highly reproducible in TmcsMed1-/- mouse heart. Collectively, these observations suggest that Med1 plays a critical role in the maintenance of heart function impacting on multiple metabolic, compensatory and reparative pathways with a likely therapeutic potential in the management of heart failure.
- Published
- 2016
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