350 results on '"Colin Sumners"'
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2. Sodium Intake and Disease: Another Relationship to Consider
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Caitlin Baumer-Harrison, Joseph M. Breza, Colin Sumners, Eric G. Krause, and Annette D. de Kloet
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sodium appetite ,taste ,blood pressure ,stress ,cardiometabolic disease ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Sodium (Na+) is crucial for numerous homeostatic processes in the body and, consequentially, its levels are tightly regulated by multiple organ systems. Sodium is acquired from the diet, commonly in the form of NaCl (table salt), and substances that contain sodium taste salty and are innately palatable at concentrations that are advantageous to physiological homeostasis. The importance of sodium homeostasis is reflected by sodium appetite, an “all-hands-on-deck” response involving the brain, multiple peripheral organ systems, and endocrine factors, to increase sodium intake and replenish sodium levels in times of depletion. Visceral sensory information and endocrine signals are integrated by the brain to regulate sodium intake. Dysregulation of the systems involved can lead to sodium overconsumption, which numerous studies have considered causal for the development of diseases, such as hypertension. The purpose here is to consider the inverse—how disease impacts sodium intake, with a focus on stress-related and cardiometabolic diseases. Our proposition is that such diseases contribute to an increase in sodium intake, potentially eliciting a vicious cycle toward disease exacerbation. First, we describe the mechanism(s) that regulate each of these processes independently. Then, we highlight the points of overlap and integration of these processes. We propose that the analogous neural circuitry involved in regulating sodium intake and blood pressure, at least in part, underlies the reciprocal relationship between neural control of these functions. Finally, we conclude with a discussion on how stress-related and cardiometabolic diseases influence these circuitries to alter the consumption of sodium.
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- 2023
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3. Angiotensin Type 2 Receptors: Painful, or Not?
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Lakshmi Pulakat and Colin Sumners
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neuropathic pain ,angiotensin type 2 receptor ,TRPA1 ,acute nerve injury ,angiotensin type 2 receptors agonism ,reactive oxygen species ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Pain in response to various types of acute injury can be a protective stimulus to prevent the organism from using the injured part and allow tissue repair and healing. On the other hand, neuropathic pain, defined as ‘pain caused by a lesion or disease of the somatosensory nervous system’, is a debilitating pathology. The TRPA1 neurons in the Dorsal Root Ganglion (DRG) respond to reactive oxygen species (ROS) and induce pain. In acute nerve injury and inflammation, macrophages infiltrating the site of injury undergo an oxidative burst, and generate ROS that promote tissue repair and induce pain via TRPA1. The latter discourages using the injured limb, with a lack of movement helping wound healing. In chronic inflammation caused by diabetes, cancer etc., ROS levels increase systemically and modulate TRPA1 neuronal functions and cause debilitating neuropathic pain. It is important to distinguish between drug targets that elicit protective vs. debilitating pain when developing effective drugs for neuropathic pain. In this context, the connection of the Angiotensin type 2 receptor (AT2R) to neuropathic pain presents an interesting dilemma. Several lines of evidence show that AT2R activation promotes anti-inflammatory and anti-nociceptive signaling, tissue repair, and suppresses ROS in chronic inflammatory models. Conversely, some studies suggest that AT2R antagonists are anti-nociceptive and therefore AT2R is a drug target for neuropathic pain. However, AT2R expression in nociceptive neurons is lacking, indicating that neuronal AT2R is not involved in neuropathic pain. It is also important to consider that Novartis terminated their phase II clinical trial (EMPHENE) to validate that AT2R antagonist EMA401 mitigates post-herpetic neuralgia. This trial, conducted in Australia, United Kingdom, and a number of European and Asian countries in 2019, was discontinued due to pre-clinical drug toxicity data. Moreover, early data from the trial did not show statistically significant positive outcomes. These facts suggest that may AT2R not be the proper drug target for neuropathic pain in humans and its inhibition can be harmful.
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- 2020
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4. Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer
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Nana Pei, Yingying Mao, Pengfei Wan, Xinglu Chen, Andrew Li, Huiying Chen, Jinlong Li, Renqiang Wan, Yanling Zhang, Hongyan Du, Baihong Chen, Guangyu Jiang, Minghan Xia, Colin Sumners, Guixue Hu, Dongsheng Gu, and Hongwei Li
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Bladder cancer (BCa) is the ninth most common form of cancer in the world. There is a continuing need not only for improving the accuracy of diagnostic markers but also for the development of new treatment strategies. Recent studies have shown that the renin-angiotensin system (RAS), which include the angiotensin type 1 (AT1R), type 2(AT2R), and Mas receptors, play an important role in tumorigenesis and may guide us in meeting those needs. Results In this study, we first observed that AT1R and Mas expression levels were significantly upregulated in BCa specimens while AT2R was significantly downregulated. Viral vector mediated overexpression of AT2R induced apoptosis and dramatically suppressed BCa cell proliferation in vitro, suggesting a therapeutic effect. Investigation into the mechanism revealed that the overexpression of AT2R increases the expression levels of caspase-3, caspase-8, and p38 and decreases the expression level of pErk. AT2R overexpression also leads to upregulation of 2 apoptosis-related genes (BCL2A1, TNFSF25) and downregulation of 8 apoptosis-related genes (CASP 6, CASP 9, DFFA, IGF1R, PYCARD, TNF, TNFRSF21, TNFSF10, NAIP) in transduced EJ cells as determined by PCR Array analysis. In vivo, we observed that AT2R overexpression caused significant reduction in xenograft tumors sizes by downregulation VEGF and induction of apoptosis. Conclusions Taken together, the data suggest that AT1R, AT2R or Mas could be used as a diagnostic marker of BCa and AT2R is a promising novel target gene for BCa gene therapy.
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- 2017
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5. The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury
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Anandharajan Rathinasabapathy, Alana Horowitz, Kelsey Horton, Ashok Kumar, Santhi Gladson, Thomas Unger, Diana Martinez, Gaurav Bedse, James West, Mohan K. Raizada, Ulrike M. Steckelings, Colin Sumners, Michael J. Katovich, and Vinayak Shenoy
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pulmonary fibrosis ,pulmonary hypertension ,C21 ,AT2 receptor ,bleomycin ,rats ,Physiology ,QP1-981 - Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT2) receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21), a selective AT2 receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg) to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip) either immediately (prevention protocol, BCP) or after 3 days (treatment protocol, BCT) of bleomycin-instillation. Echocardiography, hemodynamic, and Fulton's index assessments were performed after 2 weeks of bleomycin-instillation. Lung tissue was processed for gene expression, hydroxyproline content (a marker of collagen deposition), and histological analysis. C21 treatment prevented as well as attenuated the progression of lung fibrosis, and accompanying PH. The beneficial effects of C21 were associated with decreased infiltration of macrophages in the lungs, reduced lung inflammation and diminished pulmonary collagen accumulation. Further, C21 treatment also improved pulmonary pressure, reduced muscularization of the pulmonary vessels and normalized cardiac function in both the experimental protocols. However, there were no major differences in any of the outcomes measured from the two experimental protocols. Collectively, our findings indicate that stimulation of the AT2 receptor by C21 attenuates bleomycin-induced lung injury and associated cardiopulmonary pathology, which needs to be further explored as a promising approach for the clinical treatment of IPF and Group III PH.
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- 2018
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6. Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.
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Douglas M Bennion, Jacob D Isenberg, Allison T Harmel, Kelly DeMars, Alex N Dang, Chad H Jones, Megan E Pignataro, Justin T Graham, U Muscha Steckelings, Jon C Alexander, Marcelo Febo, Eric G Krause, Annette D de Kloet, Eduardo Candelario-Jalil, and Colin Sumners
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Medicine ,Science - Abstract
Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg) after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia.
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- 2017
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7. Direct pro-inflammatory effects of prorenin on microglia.
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Peng Shi, Justin L Grobe, Fiona A Desland, Guannan Zhou, Xiao Z Shen, Zhiying Shan, Meng Liu, Mohan K Raizada, and Colin Sumners
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Medicine ,Science - Abstract
Neuroinflammation has been implicated in hypertension, and microglia have been proposed to play an important role in the progression of this disease. Here, we have studied whether microglia are activated within cardiovascular regulatory area(s) of the brain during hypertension, especially in high blood pressure that is associated with chronic activation of the renin-angiotensin-system. In addition, we determined whether prorenin, an essential component of the renin-angiotensin-system, exerts direct pro-inflammatory effects on these microglia. Our data indicate that two rodent models which display neurogenic hypertension and over activation of the renin-angiotensin-system in the brain (sRA mice and spontaneously hypertensive rats) exhibit microglial activation, and increased levels of pro-inflammatory cytokines, in the paraventricular nucleus of the hypothalamus, an area crucial for regulation of sympathetic outflow. Further, the renin-angiotensin-system component prorenin elicits direct activation of hypothalamic microglia in culture and induction of pro-inflammatory mechanisms in these cells, effects that involve prorenin receptor-induced NFκB activation. In addition, the prorenin-elicited increases in cytokine expression were fully abolished by microglial inhibitor minocycline, and were potentiated by pre-treatment of cells with angiotensin II. Taken together with our previous data which indicate that pro-inflammatory processes in the paraventricular nucleus are involved in the hypertensive action of renin-angiotensin-system, the novel discovery that prorenin exerts direct stimulatory effects on microglial activation and pro-inflammatory cytokine production provides support for the idea that renin-angiotensin-system -induced neurogenic hypertension is not restricted to actions of angiotensin II alone.
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- 2014
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8. Gene expression profiling associated with angiotensin II type 2 receptor-induced apoptosis in human prostate cancer cells.
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Nana Pei, Feilong Jie, Jie Luo, Renqiang Wan, Yanling Zhang, Xinglu Chen, Zhibing Liang, Hongyan Du, Andrew Li, Baihong Chen, Yi Zhang, Colin Sumners, Jinlong Li, Weiwang Gu, and Hongwei Li
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Medicine ,Science - Abstract
Increased expression of angiotensin II type 2 receptor (AT2R) induces apoptosis in numerous tumor cell lines, with either Angiotensin II-dependent or Angiotensin II-independent regulation, but its molecular mechanism remains poorly understood. Here, we used PCR Array analysis to determine the gene and microRNA expression profiles in human prostate cancer cell lines transduced with AT2R recombinant adenovirus. Our results demonstrated that AT2R over expression leads to up-regulation of 6 apoptosis-related genes (TRAIL-R2, BAG3, BNIPI, HRK, Gadd45a, TP53BP2), 2 cytokine genes (IL6 and IL8) and 1 microRNA, and down-regulation of 1 apoptosis-related gene TNFSF10 and 2 cytokine genes (BMP6, BMP7) in transduced DU145 cells. HRK was identified as an up-regulated gene in AT2R-transduced PC-3 cells by real-time RT-PCR. Next, we utilized siRNAs to silence the up-regulated genes to further determine their roles on AT2R overexpression mediated apoptosis. The results showed downregulation of Gadd45a reduced the apoptotic effect by ∼30% in DU145 cells, downregulation of HRK reduced AT2R-mediated apoptosis by more than 50% in PC-3 cells, while downregulation of TRAIL-R2 enhanced AT2R-mediated apoptosis more than 4 times in DU145 cells. We also found that the effects on AT2R-mediated apoptosis caused by downregulation of Gadd45a, TRAIL-R2 and HRK were independent in activation of p38 MAPK, p44/42 MAPK and p53. Taken together, our results demonstrated that TRAIL-R2, Gadd45a and HRK may be novel target genes for further study of the mechanism of AT2R-mediated apoptosis in prostate cancer cells.
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- 2014
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9. Effects of angiotensin II type 2 receptor overexpression on the growth of hepatocellular carcinoma cells in vitro and in vivo.
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Hongyan Du, Zhibing Liang, Yanling Zhang, Feilong Jie, Jinlong Li, Yang Fei, Zhi Huang, Nana Pei, Suihai Wang, Andrew Li, Baihong Chen, Yi Zhang, Colin Sumners, Ming Li, and Hongwei Li
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Medicine ,Science - Abstract
Increasing evidence suggests that the renin-angiotensin system (RAS) plays an important role in tumorigenesis. The interaction between Angiotensin II (AngII) and angiotensin type 1 receptor (AT1R) may have a pivotal role in hepatocellular carcinoma (HCC) and therefore, AT1R blocker and angiotensin I-converting enzyme (ACE) inhibitors may have therapeutic potential in the treatment of hepatic cancer. Although the involvement of AT1R has been well explored, the role of the angiotensin II Type 2 receptor (AT2R) in HCC progression remains poorly understood. Thus, the aim of this study was to explore the effects of AT2R overexpression on HCC cells in vitro and in mouse models of human HCC. An AT2R recombinant adenoviral vector (Ad-G-AT2R-EGFP) was transduced into HCC cell lines and orthotopic tumor grafts. The results indicate that the high dose of Ad-G-AT2R-EGFP-induced overexpression of AT2R in transduced HCC cell lines produced apoptosis. AT2R overexpression in SMMC7721 cells inhibited cell proliferation with a significant reduction of S-phase cells and an enrichment of G1-phase cells through changing expression of CDK4 and cyclinD1. The data also indicate that overexpression of AT2R led to apoptosis via cell death signaling pathway that is dependent on activation of p38 MAPK, pJNK, caspase-8 and caspase-3 and inactivation of pp42/44 MAPK (Erk1/2). Finally, we demonstrated that moderately increasing AT2R expression could increase the growth of HCC tumors and the proliferation of HCC cells in vivo. Our findings suggest that AT2R overexpression regulates proliferation of hepatocellular carcinoma cells in vitro and in vivo, and the precise mechanisms of this phenomenon are yet to be fully determined.
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- 2013
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10. Quantitative Phosphoproteomics of the Angiotensin AT 2 -Receptor Signaling Network Identifies HDAC1 (Histone-Deacetylase-1) and p53 as Mediators of Antiproliferation and Apoptosis
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A. Augusto Peluso, Stefan J. Kempf, Thiago Verano-Braga, Lucas Rodrigues-Ribeiro, Lene Egedal Johansen, Mie Rytz Hansen, Gitte Kitlen, Andreas Houe Haugaard, Colin Sumners, Henrik J. Ditzel, Robson A. Santos, Michael Bader, Martin R. Larsen, and U. Muscha Steckelings
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Internal Medicine - Abstract
Background: Angiotensin AT 2 -receptor signaling is atypical for a G-protein coupled receptor and incompletely understood. To obtain novel insights into AT 2 -receptor signaling, we mapped changes in the phosphorylation status of the entire proteome of human aortic endothelial cells in response to AT 2 -receptor stimulation. Methods: Phosphorylation status of human aortic endothelial cells after stimulation with C21 (1 µM; 0, 1, 3, 5, 20 minutes) was determined utilizing time-resolved quantitative phosphoproteomics. Specific changes in protein phosphorylation and acetylation were confirmed by Western Blotting. Functional tests included resazurin assay for cell proliferation, and caspase 3/7 luminescence assay or FACS analysis of annexin V expression for apoptosis. Results: AT 2 -receptor stimulation significantly altered the phosphorylation status of 172 proteins (46% phosphorylations, 54% dephosphorylations). Bioinformatic analysis revealed a cluster of phospho-modified proteins involved in antiproliferation and apoptosis. Among these proteins, HDAC1 (histone-deacetylase-1) was dephosphorylated at serine 421/423 involving serine/threonine phosphatases. Resulting HDAC1 inhibition led to p53 acetylation and activation. AT 2 -receptor stimulation induced antiproliferation and apoptosis, which were absent when cells were co-incubated with the p53 inhibitor pifithrin-α, thus indicating p53-dependence of these AT 2 -receptor mediated functions. Conclusions: Contrary to the prevailing view that AT 2 -receptor signaling largely involves phosphatases, our study revealed significant involvement of kinases. HDAC1 inhibition and resulting p53 activation were identified as novel, AT 2 -receptor coupled signaling mechanisms. Furthermore, the study created an openly available dataset of AT 2 -receptor induced phospho-modified proteins, which has the potential to be the basis for further discoveries of currently unknown, AT 2 -receptor coupled signaling mechanisms.
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- 2022
11. The Angiotensin AT2Receptor: From a Binding Site to a Novel Therapeutic Target
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U. Muscha Steckelings, Robert E. Widdop, Edward D. Sturrock, Lizelle Lubbe, Tahir Hussain, Elena Kaschina, Thomas Unger, Anders Hallberg, Robert M. Carey, and Colin Sumners
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Renin-Angiotensin System ,Pharmacology ,Angiotensin ,Binding Sites ,Type 2/metabolism ,Humans ,Molecular Medicine ,Angiotensins/metabolism ,Type 1/metabolism ,Ligands ,Peptides/chemistry ,Receptor - Abstract
Discovered more than 30 years ago, the angiotensin AT2 receptor (AT2R) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The AT2R represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the AT2R, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the AT2R, including its structure, intracellular signaling, homo- and heterodimerization, and expression. AT2R-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the AT2R and its abundant protective effects in multiple experimental disease models and expound on AT2R ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for AT2R research. SIGNIFICANCE STATEMENT: The angiotensin AT2 receptor (AT2R) is now regarded as a fully functional and important component of the renin-angiotensin system, with the potential of exerting protective actions in a variety of diseases. This review provides an in-depth view of the AT2R, which has progressed from being an enigma to becoming a therapeutic target.
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- 2022
12. Angiotensin Receptors - Affinity and Beyond
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Igor Maciel Souza-Silva, Colin Sumners, and Ulrike Muscha Steckelings
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Renin-Angiotensin System ,Receptors, Angiotensin ,Angiotensin II ,General Medicine ,Peptides - Abstract
This commentary on the article “Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors” by Sanja Bosnyak et al. (Clini. Sci. (Lond.) (2011) 121(7): 297–303. https://doi.org/10.1042/CS20110036) summarises the main findings of the study, followed by a discussion of the findings and their relevance for various aspects of the biology of receptors of the renin-angiotensin system in the context of the current state of knowledge.
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- 2022
13. Data from Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts
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Hongwei Li, Haifa Zheng, Colin Sumners, Michael J. Katovich, Yi Zhang, Yanfei Qi, Wenjin Wei, Baihong Chen, Hongyan Du, Jinlong Li, Yanling Zhang, Andrew Li, Xinglu Chen, Renqiang Wan, and Nana Pei
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Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, heptapeptide hormone acting through the Mas receptor (MasR), with antiproliferative and antiangiogenic properties. Recent studies have shown that Ang-(1-7) has an antiproliferative action on lung adenocarcinoma cells and prostate cancer cells. In this study, we report that MasR levels were significantly upregulated in nasopharyngeal carcinoma (NPC) specimens and NPC cell lines. Viral vector–mediated expression of Ang-(1-7) dramatically suppressed NPC cell proliferation and migration in vitro. These effects were completely blocked by the specific Ang-(1-7) receptor antagonist A-779, suggesting that they are mediated by the Ang-(1-7) receptor Mas. In this study, Ang-(1-7) not only caused a significant reduction in the growth of human nasopharyngeal xenografts, but also markedly decreased vessel density, suggesting that the heptapeptide inhibits angiogenesis to reduce tumor size. Mechanistic investigations revealed that Ang-(1-7) inhibited the expression of the proangiogenic factors VEGF and PlGF. Taken together, the data suggest that upregulation of MasR could be used as a diagnostic marker of NPC and Ang-(1-7) may be a novel therapeutic agent for nasopharyngeal cancer therapy because it exerts significant antiangiogenic activity. Mol Cancer Ther; 15(1); 37–47. ©2015 AACR.
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- 2023
14. Supplemental Figure S1 from Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts
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Hongwei Li, Haifa Zheng, Colin Sumners, Michael J. Katovich, Yi Zhang, Yanfei Qi, Wenjin Wei, Baihong Chen, Hongyan Du, Jinlong Li, Yanling Zhang, Andrew Li, Xinglu Chen, Renqiang Wan, and Nana Pei
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Supplemental Figure S1. Ang-(1-7) inhibited migration of NPC cells.
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- 2023
15. Supplemental Table S1 from Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts
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Hongwei Li, Haifa Zheng, Colin Sumners, Michael J. Katovich, Yi Zhang, Yanfei Qi, Wenjin Wei, Baihong Chen, Hongyan Du, Jinlong Li, Yanling Zhang, Andrew Li, Xinglu Chen, Renqiang Wan, and Nana Pei
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Supplemental Table S1. Primers for real-time RT-PCR
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- 2023
16. Abstract 060: Angiotensin Type-2 Receptors In The Median Preoptic Nucleus Demarcate A Novel Depressor Neural Circuit In Mice
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Khalid Elsaafien, Sophia A Eikenberry, Scott W Harden, Wanhui Sheng, Karen A Scott, Charles J Frazier, Colin Sumners, Eric G Krause, and Annette D De Kloet
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Internal Medicine - Abstract
Blood pressure (BP) is under constant control and regulation by an extensive neural network that spans a number of brain regions. This includes the median preoptic nucleus (MnPO) which directly projects to the pre-autonomic neurons of the hypothalamus to increase BP. While angiotensin type-1 receptors (AT 1 R) are expressed in the MnPO and project to the hypothalamus to increase BP, the role of angiotensin type-2 receptors (AT 2 R) is not clear. Here, we combine the use of AT 2 R-Cre mice, neuroanatomical techniques, in vivo optogenetics, pharmacology, and cardiovascular physiology to test the hypothesis that AT 2 R neurons of MnPO (MnPO AT2R ) elicit cardioprotective effects. We found an abundance of AT 2 R-containing neurons in the MnPO that expressed the mRNA(s) for AT 2 R with high fidelity (~77%; 241 of 313 neurons; n=7). Using RNAscope in situ hybridization, we found that ~ 42% (153 of 364 neurons; n=8) of MnPO AT2R expressed genetic markers for GABA, an inhibitory neurotransmitter. Next, we delivered a Cre-inducible AAV to direct expression of channelrhodopsin-2 (ChR2) and/or enhanced yellow fluorescent protein (eYFP) within MnPO AT2R of AT 2 R-Cre mice. Using in vitro electrophysiology, we confirmed functional expression of ChR2 within MnPO AT2R , with pulses of light reliably producing action potentials (n= 12 neurons/3 animals). Subsequently, we found that activation of MnPO AT2R elicited inhibitory post-synaptic currents in neighboring AT 2 R-negative neurons. The in vivo optogenetic excitation of MnPO AT2R elicited depressor responses in both adult male (ΔSBP: +2.8 ± 1.3 vs. -4.1 ± 1.9 mmHg, p2 R-mediated, we administered the selective AT 2 R-agonist, compound 21, into the MnPO and observed depressor responses (ΔSBP: +0.5 ± 0.3 vs.-4.9 ± 1.0 mmHg, pAT2R are depressor inhibitory neurons that can be targeted with compound 21 to lower blood pressure.
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- 2022
17. Abstract 116: Proof Of Biological Activity And Exploration Of Early Signaling Events Of Angiotensin-(1-5)
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Igor M Silva, Augusto Peluso, Arkadiusz Nawrocki, Lene A Jakobsen, Pia Jensen, Lucas R Ribeiro, Christina Mortensen, Colin Sumners, Thiago Verano-Braga, Martin Larsen, and Ulrike M Steckelings
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Internal Medicine - Abstract
Introduction: Recombinant human ACE2 increases the circulating levels of angiotensin-(1-5) [Ang-(1-5)], a peptide thus far regarded as biologically inactive. Since ACE2 is a central component of the protective RAS, we hypothesized that Ang-(1-5) is a new biologically active peptide within this hormonal system. Objective: To investigate biological activity and signaling mechanisms of Ang-(1-5). Methods: In order to show a biological effect and to test whether Ang-(1-5) signals through the AT 2 -receptor (AT 2 R), nitric oxide (NO) release was measured by DAF-FM fluorescence in AT 2 R transfected (AT 2 R-CHO) or non-transfected (NT-CHO) CHO cells, treated with Ang-(1-5) or C21 (AT 2 R agonist, positive control) (0.1nM to 10μM) for 15 minutes. Vehicle (cell media) treated cells served as negative control. To investigate Ang-(1-5) signaling patterns, human aortic endothelial cells (HAEC) were treated with vehicle or Ang-(1-5) (1μM) for 1, 3, 5 or 20 minutes. Proteins were harvested, digested and labeled with TMTpro-16plex. Phosphopeptide enrichment was carried out by TiO 2 . Samples were subjected to LC-MS/MS analysis and the resulting mass spectra were searched against the human SwissProt database. Results: Ang-(1-5) induced a concentration-dependent increase in NO production in AT 2 -CHO cells (E max : 65.60 ± 14.02%), thus proving its biological activity. Ang-(1-5) had 69% higher efficacy than the established AT 2 R agonist C21 (E max : 38.76 ± 10.24%). Ang-(1-5) seems to signal through the AT 2 R, because effects on NO release were absent in NT-CHO cells. Treatment of HAEC with Ang-(1-5) significantly modified the phosphorylation status of 831 proteins at 1799 residues. The majority of residues (1079) were dephosphorylated while 729 residues were phosphorylated. Changes in protein phosphorylation in response to Ang-(1-5) occurred at all investigated time points, most of them after 20 minutes. Functional bioinformatic analysis revealed a cluster of proteins involved in cell cycle and cell division regulation. Conclusion: This study provides evidence that Ang-(1-5) is an endogenous AT 2 R agonist with high efficacy towards the AT 2 R. The early signaling phosphorylation pattern resembles those of other protective RAS agonists, such as C21 and Ang-(1-7).
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- 2022
18. Targeting angiotensin type-2 receptors located on pressor neurons in the nucleus of the solitary tract to relieve hypertension in mice
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Eliot A. Spector, Dominique Johnson, U. Muscha Steckelings, Wanhui Sheng, Michael Bader, Khalid Elsaafien, Colin Sumners, Scott W Harden, Charles J. Frazier, Lei Wang, Mazher Mohammed, Eric G. Krause, Karen A. Scott, and Annette D. de Kloet
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Agonist ,Physiology ,medicine.drug_class ,Stimulation ,Thiophenes ,Optogenetics ,Receptor, Angiotensin, Type 2 ,GABA ,Mice ,Physiology (medical) ,Renin–angiotensin system ,Solitary Nucleus ,Animals ,Medicine ,Receptor ,Neurons ,Sulfonamides ,business.industry ,Imidazoles ,Solitary tract ,Original Articles ,Baroreflex ,Hindbrain ,Blood pressure ,nervous system ,Hypertension ,GABAergic ,Cardiology and Cardiovascular Medicine ,business ,Neuroscience ,RAS - Abstract
Aims These studies evaluate whether angiotensin type-2 receptors (AT2Rs) that are expressed on γ-aminobutyric acid (GABA) neurons in the nucleus of the solitary tract (NTS) represent a novel endogenous blood pressure lowering mechanism. Methods and results Experiments combined advanced genetic and neuroanatomical techniques, pharmacology, electrophysiology and optogenetics in mice to define the structure and cardiovascular-related function of NTS neurons that contain AT2R. Using mice with Cre-recombinase directed to the AT2R gene, we discovered that optogenetic stimulation of AT2R-expressing neurons in the NTS increases GABA release and blood pressure. To evaluate the role of the receptor, per se, in cardiovascular regulation, we chronically delivered C21, a selective AT2R agonist, into the brains of normotensive mice and found that central AT2R activation reduces GABA-related gene expression and blunts the pressor responses induced by optogenetic excitation of NTS AT2R neurons. Next, using in situ hybridization, we found that the levels of Agtr2 mRNAs in GABAergic NTS neurons rise during experimentally-induced hypertension, and we hypothesized that this increased expression may be exploited to ameliorate the disease. Consistent with this, final experiments revealed that central administration of C21 attenuates hypertension, an effect that is abolished in mice lacking AT2R in GABAergic NTS neurons. Conclusions These studies unveil novel hindbrain circuits that maintain arterial blood pressure, and reveal a specific population of AT2R that can be engaged to alleviate hypertension. The implication is that these discrete receptors may serve as an access point for activating an endogenous depressor circuit. Translational perspective Hypertension is a widespread health problem and risk factor for cardiovascular disease and stroke. Although treatment options exist, many patients suffer from resistant hypertension, which is associated with enhanced sympathetic drive. Thus, many available therapeutics focus on dampening pressor mechanisms. The present studies take the alternative approach of treating hypertension by exploiting an endogenous depressor mechanism.
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- 2021
19. The Renin-Angiotensin System in Hypertension, a Constantly Renewing Classic: Focus on the Angiotensin AT2-Receptor
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Kasper Bostlund Assersen, Colin Sumners, and U. Muscha Steckelings
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Endothelium ,business.industry ,Central nervous system ,030204 cardiovascular system & hematology ,medicine.disease ,Angiotensin II ,Preeclampsia ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Blood pressure ,medicine.anatomical_structure ,Renin–angiotensin system ,medicine ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,Receptor ,Neuroscience - Abstract
It is common knowledge that the renin-angiotensin system (RAS), in particular angiotensin II acting through the angiotensin AT1-receptor (AT1R), is pivotal for the regulation of blood pressure (BP) and extracellular volume. More recent findings have revealed that the RAS is far more complex than initially thought and that it harbours additional mediators and receptors, which are able to counteract and thereby fine-tune AT1R-mediated actions. This review will focus on the angiotensin AT2-receptor (AT2R), which is one of the "counter-regulatory" receptors within the RAS. It will review and discuss data related to the role of the AT2R in regulation of BP and focus on the following 3 questions: Do peripheral AT2R have an impact on BP regulation, and, if so, does this effect become apparent only under certain conditions? Are central nervous system AT2R involved in regulation of BP, and, if so, which brain areas are involved and what are the mechanisms? Does dysfunction of AT2R contribute to the pathogenesis of hypertension in preeclampsia?
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- 2020
20. PS-BPB04-6: PROOF OF BIOLOGICAL ACTIVITY AND EXPLORATION OF EARLY SIGNALING EVENTS OF ANGIOTENSIN-(1–5)
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Igor Maciel Souza Silva, Antonio Augusto Peluso, Lene Andrup Jakobsen, Pia Jensen, Lucas Rodrigues Aguiar Ribeiro, Christina Mortensen, Colin Sumners, Thiago Verano Braga, Martin Roessel Larsen, and Ulrike Muscha Steckelings
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Physiology ,Internal Medicine ,Cardiology and Cardiovascular Medicine - Published
- 2023
21. Impaired Autonomic Nervous System-Microbiome Circuit in Hypertension
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Elaine M. Richards, Seungbum Kim, Colin Sumners, Jasenka Zubcevic, Tao Yang, Carl J. Pepine, and Mohan K. Raizada
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Physiology ,business.industry ,Dysfunctional family ,Bioinformatics ,Omics ,Systemic circulation ,Gut microbiome ,Autonomic nervous system ,Blood pressure ,Medicine ,Gut dysbiosis ,Microbiome ,Cardiology and Cardiovascular Medicine ,business - Abstract
Hypertension affects an estimated 103 million Americans, yet gaps in knowledge continue to limit its successful management. Rapidly emerging evidence is linking gut dysbiosis to many disorders and diseases including hypertension. The evolution of the -omics techniques has allowed determination of the abundance and potential function of gut bacterial species by next-generation bacterial sequencing, whereas metabolomics techniques report shifts in bacterial metabolites in the systemic circulation of hypertensive patients and rodent models of hypertension. The gut microbiome and host have evolved to exist in balance and cooperation, and there is extensive crosstalk between the 2 to maintain this balance, including during regulation of blood pressure. However, an understanding of the mechanisms of dysfunctional host-microbiome interactions in hypertension is still lacking. Here, we synthesize some of our recent data with published reports and present concepts and a rationale for our emerging hypothesis of a dysfunctional gut-brain axis in hypertension. Hopefully, this new information will improve the understanding of hypertension and help to address some of these knowledge gaps.
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- 2019
22. Microglial Cells Impact Gut Microbiota and Gut Pathology in Angiotensin II-Induced Hypertension
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Elaine M. Richards, Carl J. Pepine, Seungbum Kim, Mohan K. Raizada, Ravindra K. Sharma, Tao Yang, Gilberto O Lobaton, Aline C. Oliveira, Colin Sumners, and Victor Aquino
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Male ,Physiology ,Anti-Inflammatory Agents ,Gut flora ,Autonomic Nervous System ,Rats, Inbred WKY ,Rats, Inbred SHR ,Animals ,Medicine ,Arterial Pressure ,Antihypertensive Agents ,Neuroinflammation ,biology ,Microglia ,business.industry ,Angiotensin II ,biology.organism_classification ,Anti-Bacterial Agents ,Gastrointestinal Microbiome ,Intestines ,Disease Models, Animal ,Infusions, Intraventricular ,medicine.anatomical_structure ,Tetracyclines ,Hypertension ,Immunology ,Gut dysbiosis ,Cardiology and Cardiovascular Medicine ,business ,Paraventricular Hypothalamic Nucleus - Abstract
Rationale: Increased microglial activation and neuroinflammation within autonomic brain regions have been implicated in sustained hypertension, and their inhibition by minocycline—an anti-inflammatory antibiotic—produces beneficial effects. These observations led us to propose a dysfunctional brain-gut communication hypothesis for hypertension. However, it has been difficult to reconcile whether an anti-inflammatory or antimicrobial action is the primary beneficial effect of minocycline in hypertension. Accordingly, we utilized chemically modified tetracycline-3 (CMT-3)—a derivative of tetracycline that has potent anti-inflammatory activity—to address this question. Objective: Test the hypothesis that central administration of CMT-3 would inhibit microglial activation, attenuate neuroinflammation, alter selective gut microbial communities, protect the gut wall from developing hypertension-associated pathology, and attenuate hypertension. Methods and Results: Rats were implanted with radiotelemetry devices for recording mean arterial pressure. Ang II (angiotensin II) was infused subcutaneously using osmotic mini-pumps to induce hypertension. Another osmotic mini-pump was surgically implanted to infuse CMT-3 intracerebroventricularly. Intracerebroventricular CMT- 3 infusion was also investigated in SHR (spontaneously hypertensive rats). Physiological, pathological, immunohistological parameters, and fecal microbiota were analyzed. Intracerebroventricular CMT-3 significantly inhibited Ang II-induced increases in number of microglia, their activation, and proinflammatory cytokines in the paraventricular nucleus of hypothalamus. Further, intracerebroventricular CMT-3 attenuated increased mean arterial pressure, normalized sympathetic activity, and left ventricular hypertrophy in Ang II rats, as well as in the SHR. Finally, CMT-3 beneficially restored certain gut microbial communities altered by Ang II and attenuated pathological alterations in gut wall. Conclusions: These observations demonstrate that inhibition of microglial activation alone was sufficient to induce significant antihypertensive effects. This was associated with unique changes in gut microbial communities and profound attenuation of gut pathology. They suggest, for the first time, a link between microglia and certain microbial communities that may have implications for treatment of hypertension.
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- 2019
23. Importance of AT1 and AT2 receptors in the nucleus of the solitary tract in cardiovascular responses induced by a high-fat diet
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Debora S. A. Colombari, Maria Andréia Delbin, Hongwei Li, Eduardo Colombari, Mariana Rosso Melo, José Vanderlei Menani, Guilherme Fleury Fina Speretta, Mirian Bassi, Colin Sumners, and Prashant J. Ruchaya
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Male ,medicine.medical_specialty ,Physiology ,Inflammation ,030204 cardiovascular system & hematology ,Baroreflex ,Diet, High-Fat ,Receptor, Angiotensin, Type 2 ,Article ,Receptor, Angiotensin, Type 1 ,Rats, Sprague-Dawley ,Renin-Angiotensin System ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Renin–angiotensin system ,Solitary Nucleus ,Internal Medicine ,medicine ,Animals ,Arterial Pressure ,Obesity ,030212 general & internal medicine ,Receptor ,Angiotensin II receptor type 1 ,business.industry ,Solitary tract ,respiratory system ,Rats ,Blood pressure ,Endocrinology ,nervous system ,Reflex bradycardia ,Cytokines ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Brainstem ,Angiotensin II Type 1 Receptor Blockers ,circulatory and respiratory physiology - Abstract
A high-fat diet (HFD) induces an increase in arterial pressure and a decrease in baroreflex function, which may be associated with increased expression of angiotensin type 1 receptor (AT1R) and pro-inflammatory cytokine genes and reduced expression of the angiotensin type 2 receptor (AT2R) gene within the nucleus of the solitary tract (NTS), a key area of the brainstem involved in cardiovascular control. Thus, in the present study, we evaluated the changes in arterial pressure and gene expression of components of the renin-angiotensin system (RAS) and neuroinflammatory markers in the NTS of rats fed a HFD and treated with either an AT1R blocker or with virus-mediated AT2R overexpression in the NTS. Male Holtzman rats (300-320 g) were fed either a standard rat chow diet (SD) or HFD for 6 weeks before commencing the tests. AT1R blockade in the NTS of HFD-fed rats attenuated the increase in arterial pressure and the impairment of reflex bradycardia, whereas AT2R overexpression in the NTS only improved the baroreflex function. The HFD also increased the hypertensive and decreased the protective axis of the RAS and was associated with neuroinflammation within the NTS. The expression of angiotensin-converting enzyme and neuroinflammatory components, but not AT1R, in the NTS was reduced by AT2R overexpression in this site. Based on these data, AT1R and AT2R in the NTS are differentially involved in the cardiovascular changes induced by a HFD. Chronic inflammation and changes in the RAS in the NTS may also account for the cardiovascular responses observed in HFD-fed rats.
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- 2019
24. The Angiotensin AT
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U Muscha, Steckelings, Robert E, Widdop, Edward D, Sturrock, Lizelle, Lubbe, Tahir, Hussain, Elena, Kaschina, Thomas, Unger, Anders, Hallberg, Robert M, Carey, and Colin, Sumners
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Renin-Angiotensin System ,Angiotensins ,Binding Sites ,Humans ,Ligands ,Peptides ,Receptor, Angiotensin, Type 2 ,Receptor, Angiotensin, Type 1 - Abstract
Discovered more than 30 years ago, the angiotensin AT
- Published
- 2020
25. Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists
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U. Muscha Steckelings and Colin Sumners
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Agonist ,medicine.drug_class ,Pneumonia, Viral ,Angiotensin-Converting Enzyme Inhibitors ,Inflammation ,Stimulation ,Peptidyl-Dipeptidase A ,Pharmacology ,Receptor, Angiotensin, Type 2 ,Renin-Angiotensin System ,Betacoronavirus ,Renin–angiotensin system ,medicine ,Humans ,Endothelial dysfunction ,Pandemics ,biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,Angiotensin-converting enzyme ,General Medicine ,medicine.disease ,Angiotensin II ,Angiotensin-converting enzyme 2 ,ras Proteins ,biology.protein ,Angiotensin-Converting Enzyme 2 ,medicine.symptom ,Coronavirus Infections ,business - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the global corona virus disease 2019 (COVID-19) pandemic enters host cells via a mechanism that includes binding to angiotensin converting enzyme (ACE) 2 (ACE2). Membrane-bound ACE2 is depleted as a result of this entry mechanism. The consequence is that the protective renin–angiotensin system (RAS), of which ACE2 is an essential component, is compromised through lack of production of the protective peptides angiotensin-(1-7) and angiotensin-(1-9), and therefore decreased stimulation of Mas (receptor Mas) and angiotensin AT2-receptors (AT2Rs), while angiotensin AT1-receptors (AT1Rs) are overstimulated due to less degradation of angiotensin II (Ang II) by ACE2. The protective RAS has numerous beneficial actions, including anti-inflammatory, anti-coagulative, anti-fibrotic effects along with endothelial and neural protection; opposite to the deleterious effects caused by heightened stimulation of angiotensin AT1R. Given that patients with severe COVID-19 exhibit an excessive immune response, endothelial dysfunction, increased clotting, thromboses and stroke, enhancing the activity of the protective RAS is likely beneficial. In this article, we discuss the evidence for a dysfunctional protective RAS in COVID and develop a rationale that the protective RAS imbalance in COVID-19 may be corrected by using AT2R agonists. We further review preclinical studies with AT2R agonists which suggest that AT2R stimulation may be therapeutically effective to treat COVID-19-induced disorders of various organ systems such as lung, vasculature, or the brain. Finally, we provide information on the design of a clinical trial in which patients with COVID-19 were treated with the AT2R agonist Compound 21 (C21). This trial has been completed, but results have not yet been reported.
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- 2020
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26. Brain Angiotensin Type-1 and Type-2 Receptors in Physiological and Hypertensive Conditions: Focus on Neuroinflammation
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Eric G. Krause, Khalid Elsaafien, Annette D. de Kloet, and Colin Sumners
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Angiotensin receptor ,Receptors, Angiotensin ,Microglia ,business.industry ,Brain ,030204 cardiovascular system & hematology ,Receptor, Angiotensin, Type 2 ,Receptor, Angiotensin, Type 1 ,Article ,Cardiovascular physiology ,03 medical and health sciences ,0302 clinical medicine ,Blood pressure ,medicine.anatomical_structure ,Renin–angiotensin system ,Hypertension ,Internal Medicine ,Medicine ,Humans ,030212 general & internal medicine ,Angiotensin I ,Receptor ,business ,Neuroscience ,Neuroinflammation - Abstract
PURPOSE OF REVIEW. To review recent data that suggest opposing effects of brain angiotensin type-1 (AT(1)R) and type-2 (AT(2)R) receptors on blood pressure (BP). Here, we discuss recent studies that suggest pro-hypertensive and pro-inflammatory actions of AT(1)R, and anti-hypertensive and anti-inflammatory actions of AT(2)R. Further, we propose mechanisms for the interplay between brain angiotensin receptors and neuroinflammation in hypertension. RECENT FINDINGS. The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular physiology. This includes brain AT(1)R and AT(2)R, both of which are expressed in or adjacent to brain regions that control BP. Activation of AT(1)R within those brain regions mediate increases in BP and cause neuroinflammation, which augments the BP increase in hypertension. The fact that AT(1)R and AT(2)R have opposing actions on BP, suggests that AT(1)R and AT(2)R may have similar opposing actions on neuroinflammation. However, the mechanisms by which brain AT(1)R and AT(2)R mediate neuroinflammatory responses remain unclear. SUMMARY. The interplay between brain angiotensin receptor subtypes and neuroinflammation exacerbates or protects against hypertension.
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- 2020
27. ACE2 activator diminazene aceturate reduces adiposity but preserves lean mass in young and old rats
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Erin Bruce, Christy S. Carter, Drake Morgan, Hale Z. Toklu, Philip J. Scarpace, Colin Sumners, Yasemin Sakarya, Nihal Tümer, and Nataliya Kirichenko
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Male ,0301 basic medicine ,Aging ,medicine.medical_specialty ,Gene Expression ,White adipose tissue ,Peptidyl-Dipeptidase A ,030204 cardiovascular system & hematology ,Biochemistry ,Body fat percentage ,Article ,Renin-Angiotensin System ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Renin–angiotensin system ,Genetics ,medicine ,Animals ,Diminazene aceturate ,Obesity ,Molecular Biology ,Adiposity ,Activator (genetics) ,business.industry ,Age Factors ,Cell Biology ,medicine.disease ,Peptide Fragments ,Rats, Inbred F344 ,Rats ,Disease Models, Animal ,030104 developmental biology ,Anorectic ,Lean body mass ,Angiotensin-Converting Enzyme 2 ,Angiotensin I ,business ,Diminazene - Abstract
The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2]/angiotensin-(1-7)[Ang-(1-7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23 months, respectively) male Fisher 344 × Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15 mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD-NMR assessments revealed that the weight-loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang-(1-7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved.
- Published
- 2018
28. Neuroprotection by post-stroke administration of an oral formulation of angiotensin-(1-7) in ischaemic stroke
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Frederico B. De Sousa, Robson A.S. Santos, Alex Dang, Lauren L. Donnangelo, Douglas M. Bennion, Rubén D. Sinisterra, Justin T Graham, Jacob D Isenberg, Vermali Rodriguez, Chad H Jones, and Colin Sumners
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Male ,medicine.medical_specialty ,Ischemia ,Blood Pressure ,030204 cardiovascular system & hematology ,Tissue plasminogen activator ,Neuroprotection ,Rats, Sprague-Dawley ,Renin-Angiotensin System ,03 medical and health sciences ,0302 clinical medicine ,Oral administration ,Internal medicine ,medicine ,Animals ,Stroke ,Endothelin-1 ,business.industry ,Infarction, Middle Cerebral Artery ,General Medicine ,medicine.disease ,Peptide Fragments ,2-Hydroxypropyl-beta-cyclodextrin ,Rats ,Neuroprotective Agents ,Blood pressure ,Cerebral blood flow ,Cerebrovascular Circulation ,Systemic administration ,Cardiology ,Angiotensin I ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
NEW FINDINGS What is the central question of this study? Angiotensin-(1-7) decreases cerebral infarct volume and improves neurological function when delivered centrally before and during ischaemic stroke. Here, we assessed the neuroprotective effects of angiotensin-(1-7) when delivered orally post-stroke. What is the main finding and its importance? We show that oral delivery of angiotensin-(1-7) attenuates cerebral damage induced by middle cerebral artery occlusion in rats, without affecting blood pressure or cerebral blood flow. Importantly, these treatments begin post-stroke at times coincident with the treatment window for tissue plasminogen activator, providing supporting evidence for clinical translation of this new therapeutic strategy. ABSTRACT As a target for stroke therapies, the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas [ACE2/Ang-(1-7)/Mas] axis of the renin-angiotensin system can be activated chronically to induce neuroprotective effects, in opposition to the deleterious effects of angiotensin II via its type 1 receptor. However, more clinically relevant treatment protocols with Ang-(1-7) that involve its systemic administration beginning after the onset of ischaemia have not been tested. In this study, we tested systemic post-stroke treatments using a molecule where Ang-(1-7) is included within hydroxypropyl-β-cyclodextrin [HPβCD-Ang-(1-7)] as an orally bioavailable treatment. In three separate protocols, HPβCD-Ang-(1-7) was administered orally to Sprague-Dawley rats after induction of ischaemic stroke by endothelin-1-induced middle cerebral artery occlusion: (i) to assess its effects on cerebral damage and behavioural deficits; (ii) to determine its effects on cardiovascular parameters; and (iii) to determine whether it altered cerebral blood flow. The results indicate that post-stroke oral administration of HPβCD-Ang-(1-7) resulted in 25% reductions in cerebral infarct volumes and improvement in neurological functions (P
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- 2018
29. Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach
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Oliver Domenig, Chad H Jones, Alex Dang, Lena Lindblad, Colin Sumners, Marko Poglitsch, Douglas M. Bennion, Michael F. Waters, Jacob D Isenberg, Ulrike Muscha Steckelings, and Justin T Graham
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Agonist ,medicine.drug_class ,business.industry ,Central nervous system ,General Medicine ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease ,Neuroprotection ,Angiotensin II ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Renin–angiotensin system ,Journal Article ,medicine ,Systemic administration ,Receptor ,business ,Stroke ,030217 neurology & neurosurgery - Abstract
Significant neuroprotective effects of angiotensin II type 2 (AT 2 ) receptor (AT 2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT 2 receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT 2 receptor agonist Compound 21 (C21) to näive rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4-9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT 2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT 2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.
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- 2018
30. Centrally Mediated Cardiovascular Actions of the Angiotensin II Type 2 Receptor
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U. Muscha Steckelings, Annette D. de Kloet, and Colin Sumners
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Angiotensin receptor ,medicine.medical_specialty ,Sympathetic Nervous System ,vasopressin ,Endocrinology, Diabetes and Metabolism ,Blood Pressure ,Stimulation ,Review ,angiotensin II ,030204 cardiovascular system & hematology ,Cardiovascular System ,Receptor, Angiotensin, Type 2 ,Cardiovascular Physiological Phenomena ,Renin-Angiotensin System ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Renin–angiotensin system ,Journal Article ,Animals ,Humans ,Medicine ,sympathetic nervous system ,Angiotensin II receptor type 1 ,business.industry ,Brain ,Neurogenic hypertension ,medicine.disease ,Angiotensin II ,Blood pressure ,angiotensin type 2 receptor ,Pathophysiology of hypertension ,neurogenic hypertension ,business ,030217 neurology & neurosurgery - Abstract
Sustained increases in the activity of the sympathetic neural pathways that exit the brain and which increase blood pressure (BP) are a major underlying factor in resistant hypertension. Recently available information on the occurrence of angiotensin II type 2 receptors (AT2Rs) within or adjacent to brain cardiovascular control centers is consistent with findings that stimulation of these receptors lowers BP, particularly during hypertension of neurogenic origin. Until recently brain AT2R had not been considered by many to play a role in the central control of BP. Demonstration of these powerful antihypertensive effects of brain AT2R opens the door to reconsideration of their role in BP regulation, and their consideration as a novel therapeutic avenue for resistant hypertension.
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- 2017
31. Role of environmental stressors in determining the developmental outcome of neonatal anesthesia
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Timothy E. Morey, Jiao-Jiao Yang, Christoph N. Seubert, Anatoly E. Martynyuk, Jian-Jun Yang, Colin Sumners, Nikolaus Gravenstein, Terrie Vasilopoulos, and Ling-Sha Ju
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Restraint, Physical ,medicine.medical_specialty ,Corticotropin-Releasing Hormone ,Endocrinology, Diabetes and Metabolism ,Article ,03 medical and health sciences ,Corticotropin-releasing hormone ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,030202 anesthesiology ,Etomidate ,Corticosterone ,Internal medicine ,Gene expression ,medicine ,Animals ,Solute Carrier Family 12, Member 2 ,Anesthesia ,Bumetanide ,Biological Psychiatry ,Maternal deprivation ,Behavior, Animal ,Symporters ,Endocrine and Autonomic Systems ,Maternal Deprivation ,Depolarization ,Rats ,Psychiatry and Mental health ,Animals, Newborn ,chemistry ,Anesthetic ,Psychology ,Anesthetics, Intravenous ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background The majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure. Methods Postnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na+-K+-2Cl− (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2 h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3 h at P10. 3–7 days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K+-2Cl− (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects. Conclusions Post-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation.
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- 2017
32. Small-molecule AT2 receptor agonists
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Mathias Hallberg, Colin Sumners, Anders Hallberg, and U. Muscha Steckelings
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Agonist ,Peptidomimetic ,Stereochemistry ,medicine.drug_class ,Review ,Angiotensin II Type 2 Receptor Blockers ,030204 cardiovascular system & hematology ,Ligands ,Receptor, Angiotensin, Type 2 ,Small Molecule Libraries ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Drug Discovery ,Journal Article ,medicine ,Animals ,Humans ,Imidazole ,Methylene ,Receptor ,Pharmacology ,Small molecule ,Angiotensin II ,chemistry ,Molecular Medicine ,030217 neurology & neurosurgery - Abstract
The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (Ki = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.
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- 2017
33. Increased Expression of Macrophage Migration Inhibitory Factor in the Nucleus of the Solitary Tract Attenuates Renovascular Hypertension in Rats
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Hongwei Li, José Vanderlei Menani, Guilherme Fleury Fina Speretta, Daniel Penteado Martins Dias, Rafaela Moreira Barbosa, Debora S. A. Colombari, Colin Sumners, Prashant J. Ruchaya, Eduardo Colombari, Universidade Estadual Paulista (Unesp), Universidade de São Paulo (USP), Southern Med Univ, and Univ Florida
- Subjects
Male ,medicine.medical_specialty ,Mean arterial pressure ,hypertension ,Drinking Behavior ,angiotensin II ,030204 cardiovascular system & hematology ,Baroreflex ,brainstem ,Renovascular hypertension ,Rats, Sprague-Dawley ,Eating ,03 medical and health sciences ,Renal Artery ,0302 clinical medicine ,Heart Rate ,Internal medicine ,Solitary Nucleus ,Internal Medicine ,medicine ,Animals ,baroreflex ,Arterial Pressure ,Gene Knock-In Techniques ,Macrophage Migration-Inhibitory Factors ,Angiotensin II receptor type 1 ,AT1 receptor ,business.industry ,Solitary tract ,blood pressure ,respiratory system ,medicine.disease ,Angiotensin II ,Rats ,Intramolecular Oxidoreductases ,Disease Models, Animal ,Hypertension, Renovascular ,Endocrinology ,Blood pressure ,nervous system ,Original Article ,Macrophage migration inhibitory factor ,business ,2K1C ,030217 neurology & neurosurgery ,circulatory and respiratory physiology - Abstract
Made available in DSpace on 2018-11-26T17:33:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-04-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) NIH BACKGROUND Macrophage migration inhibitory factor (MIF) is an intracellular inhibitory regulator of the actions of angiotensin II in the central nervous system. Renovascular hypertensive 2-kidney, 1-clip (2K1C) rats have an increased activity of the renin-angiotensin system and a decrease in baroreflex function compared to normotensive (NT) rats. In the present study, we tested the effects of MIF overexpression within the nucleus of the solitary tract (NTS), a key brainstem region for cardiovascular regulation, on the development of hypertension, on baroreflex function, and on water and food intake in 2K1C rats. METHODS Holtzman NT rats received a silver clip around the left renal artery to induce 2K1C hypertension. Three weeks later, rats were microinjected in the NTS with AAV2-CBA-MIF, to increase the expression of MIF, or with the control vector AAV2-CBA-enhanced green fluorescent protein. Mean arterial pressure (MAP) and heart rate were recorded by telemetry. Baroreflex function was tested, and water and food intake were also measured. RESULTS Increasing MIF expression in the NTS of 2K1C rats attenuated the development of hypertension, reversed the impairment of baroreflex function, and reduced the increase in water intake. In contrast to 2K1C rats, similar increases in MIF expression in the NTS of NT rats produced no changes in baseline MAP, baroreflex function, or water intake. CONCLUSIONS These results indicate that an increased expression of MIF within the NTS attenuates the development of hypertension and restores the baroreflex function in 2K1C rats. Sao Paulo State Univ, Sch Dent, Dept Physiol & Pathol, Araraquara, SP, Brazil Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Physiol, Ribeirao Preto, SP, Brazil Southern Med Univ, Sch Biotechnol, Guangzhou, Guangdong, Peoples R China Univ Florida, Coll Med, Dept Physiol & Funct Genom, Gainesville, FL USA Sao Paulo State Univ, Sch Dent, Dept Physiol & Pathol, Araraquara, SP, Brazil CNPq: 473108/2011-9 CNPq: 304918/2011-3 FAPESP: 2011/50770-1 FAPESP: 2015/23467-7 NIH: HL-076803
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- 2017
34. AAV-Mediated angiotensin 1-7 overexpression inhibits tumor growth of lung cancer in vitro and in vivo
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Na Bai, Wang Shengyao, Hongwei Li, Nana Pei, Andrew Li, Colin Sumners, Renhe Yan, Yanling Zhang, Baihong Chen, Sansan Chen, Xinglu Chen, Hongyan Du, Jinlong Li, and Yingying Mao
- Subjects
0301 basic medicine ,Gerontology ,Vascular Endothelial Growth Factor A ,Lung Neoplasms ,Cell Cycle Proteins ,Mice ,0302 clinical medicine ,Cell Movement ,Carcinoma, Non-Small-Cell Lung ,Lung ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,Nuclear Proteins ,Dependovirus ,Immunohistochemistry ,Oncology ,030220 oncology & carcinogenesis ,Molecular mechanism ,Female ,adeno-associated viral vector ,Research Paper ,DNA Replication ,Epithelial-Mesenchymal Transition ,proliferation ,Genetic Vectors ,Down-Regulation ,Mice, Nude ,Viral vector ,03 medical and health sciences ,Ang-(1-7) ,In vivo ,Multienzyme Complexes ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Tumor growth ,Lung cancer ,Cell Proliferation ,Angiotensin 1 ,DNA synthesis ,business.industry ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Peptide Fragments ,lung cancer ,030104 developmental biology ,Lung cancer cell ,Proteolysis ,Cancer research ,Angiotensin I ,business - Abstract
// Xinglu Chen 1, * , Sansan Chen 2, * , Nana Pei 3, * , Yingying Mao 1 , Shengyao Wang 1 , Renhe Yan 1 , Na Bai 4 , Andrew Li 5 , Yanling Zhang 1 , Hongyan Du 1 , Baihong Chen 1 , Colin Sumners 6 , Jinlong Li 1 , Hongwei Li 1 1 School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China 2 Department of Urology, The First Affiliated Hospital of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, Guangdong, China 3 Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China 4 Deparement of Nuclear Medicine, People’s Hospital of Yuxi City, Yuxi, Yunnan, China 5 Department of Biomedical Engineering, The Johns University School of Medicine, Baltimore, USA 6 Departments of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, USA * These authors contributed equally to this work Correspondence to: Hongwei Li, email: hongwei1@yahoo.com Jinglong Li, email: lijinlong75@126.com Keywords: Ang-(1-7), lung cancer, adeno-associated viral vector, DNA synthesis, proliferation Received: October 07, 2016 Accepted: November 11, 2016 Published: November 16, 2016 ABSTRACT Ang-(1-7) inhibits lung cancer cell growth both in vitro and in vivo . However, the molecular mechanism of action is unclear and also the rapid degradation of Ang-(1-7) in vivo limits its clinical application. Here, we have demonstrated that Ang- (1-7) inhibits lung cancer cell growth by interrupting pre-replicative complex assembly and restrains epithelial-mesenchymal transition via Cdc6 inhibition. Furthermore, we constructed a mutant adeno-associated viral vector AAV8 (Y733F) that produced stable and high efficient Ang-(1-7) expression in a xenograft tumor model. The results show that AAV8-mediated Ang-(1-7) over-expression can remarkably suppress tumor growth in vivo by down-regulating Cdc6 and anti-angiogenesis. Ang-(1-7) over-expression via the AAV8 method may be a promising strategy for lung cancer treatment.
- Published
- 2016
35. Anti-fibrotic mechanisms of angiotensin AT2 -receptor stimulation
- Author
-
Jesper Bork Bertelsen, Colin Sumners, Ulrike Muscha Steckelings, Antonio Augusto Peluso, and Andreas Houe Haugaard
- Subjects
0301 basic medicine ,Agonist ,endocrine system ,fibrotic disease ,Physiology ,medicine.drug_class ,Stimulation ,030204 cardiovascular system & hematology ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,angiotensin AT -receptor ,Renin–angiotensin system ,medicine ,Receptor ,Relaxin ,Kidney ,Angiotensin II receptor type 1 ,business.industry ,fibrosis ,respiratory system ,angiotensin ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,cardiovascular system ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
The angiotensin AT2 -receptor is a main receptor of the protective arm of the renin-angiotensin-system. Understanding of this unconventional G-protein coupled receptor has significantly advanced during the past decade, largely because of the availability of a selective non-peptide AT2 -receptor agonist, which allowed the conduct of a multitude of studies in animal disease models. This article reviews such preclinical studies that in their entirety provide strong evidence for an anti-fibrotic effect mediated by activation of the AT2 -receptor. Prevention of the development of fibrosis by AT2 -receptor stimulation has been demonstrated in lung, heart, blood vessels, kidney, pancreas and skin. In lung, AT2 -receptor stimulation was even able to reverse existing fibrosis. The article further discusses intracellular signalling mechanisms mediating the AT2 -receptor coupled anti-fibrotic effect, including activation of phosphatases and subsequent interference with pro-fibrotic signalling pathways, induction of matrix-metalloproteinases, and hetero-dimerisation with the AT1 -receptor, the TGF-βRII-receptor or the RXFP1-receptor for relaxin. Knowledge of the anti-fibrotic effects of the AT2 -receptor is of particular relevance, because drugs targeting this receptor have entered clinical development for indications involving fibrotic diseases. This article is protected by copyright. All rights reserved.
- Published
- 2019
36. Brain angiotensin type-1 and type-2 receptors: cellular locations under normal and hypertensive conditions
- Author
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Jacob A. Ludin, Eric G. Krause, Amy R. Alleyne, Meng Liu, Annette D. de Kloet, Colin Sumners, Shormista Kar, Zachary Winder, David J. Pioquinto, Vermali Rodriguez, and Yuma T. Ortiz
- Subjects
Physiology ,Blood Pressure ,030204 cardiovascular system & hematology ,Biology ,Baroreflex ,Receptor, Angiotensin, Type 2 ,Receptor, Angiotensin, Type 1 ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Rats, Inbred SHR ,Renin–angiotensin system ,Internal Medicine ,medicine ,Animals ,030212 general & internal medicine ,Rats, Wistar ,Receptor ,Cellular localization ,Neurons ,Microglia ,Solitary tract ,Colocalization ,Brain ,Neurogenic hypertension ,Cell biology ,Rats ,medicine.anatomical_structure ,Astrocytes ,Hypertension ,Cardiology and Cardiovascular Medicine - Abstract
Brain angiotensin-II (Ang-II) type-1 receptors (AT1Rs), which exert profound effects on normal cardiovascular, fluid, and metabolic homeostasis, are overactivated in and contribute to chronic sympathoexcitation and hypertension. Accumulating evidence indicates that the activation of Ang-II type-2 receptors (AT2Rs) in the brain exerts effects that are opposite to those of AT1Rs, lowering blood pressure, and reducing hypertension. Thus, it would be interesting to understand the relative cellular localization of AT1R and AT2R in the brain under normal conditions and whether this localization changes during hypertension. Here, we developed a novel AT1aR-tdTomato reporter mouse strain in which the location of brain AT1aR was largely consistent with that determined in the previous studies. This AT1aR-tdTomato reporter mouse strain was crossed with our previously described AT2R-eGFP reporter mouse strain to yield a novel dual AT1aR/AT2R reporter mouse strain, which allowed us to determine that AT1aR and AT2R are primarily localized to different populations of neurons in brain regions controlling cardiovascular, fluid, and metabolic homeostasis. Using the individual AT1aR-tdTomato reporter mice, we also demonstrated that during hypertension induced by the administration of deoxycorticosterone acetate-salt, there was no shift in the expression of AT1aR from neurons to microglia or astrocytes in the paraventricular nucleus, a brain area important for sympathetic regulation. Using AT2R-eGFP reporter mice under similar hypertensive conditions, we demonstrated that the same was true of AT2R expression in the nucleus of the solitary tract (NTS), an area critical for baroreflex control. Collectively, these findings provided a novel means to assess the colocalization of AT1R and AT2R in the brain and a novel view of their cellular localization in hypertension.
- Published
- 2019
37. Impaired Autonomic Nervous System-Microbiome Circuit in Hypertension
- Author
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Jasenka, Zubcevic, Elaine M, Richards, Tao, Yang, Seungbum, Kim, Colin, Sumners, Carl J, Pepine, and Mohan K, Raizada
- Subjects
Gastrointestinal Tract ,Hypertension ,Animals ,Humans ,Blood Pressure ,Autonomic Nervous System ,Article ,Gastrointestinal Microbiome - Abstract
Hypertension affects an estimated 103 million Americans, yet gaps in knowledge continue to limit its successful management. Rapidly emerging evidence is linking gut dysbiosis to many disorders and diseases including hypertension. The evolution of the -omics techniques has allowed determination of the abundance and potential function of gut bacterial species by next-generation bacterial sequencing, whereas metabolomics techniques report shifts in bacterial metabolites in the systemic circulation of hypertensive patients and rodent models of hypertension. The gut microbiome and host have evolved to exist in balance and cooperation, and there is extensive crosstalk between the 2 to maintain this balance, including during regulation of blood pressure. However, an understanding of the mechanisms of dysfunctional host-microbiome interactions in hypertension is still lacking. Here, we synthesize some of our recent data with published reports and present concepts and a rationale for our emerging hypothesis of a dysfunctional gut-brain axis in hypertension. Hopefully, this new information will improve the understanding of hypertension and help to address some of these knowledge gaps.
- Published
- 2019
38. Angiotensin receptor expression revealed by reporter mice and beneficial effects of AT2R agonist in retinal cells
- Author
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Eric G. Krause, Annette D. de Kloet, Ping Zhu, Amrisha Verma, Qiuhong Li, and Colin Sumners
- Subjects
Agonist ,Angiotensin receptor ,medicine.drug_class ,Cell Survival ,Mice, Transgenic ,Retinal Pigment Epithelium ,Thiophenes ,medicine.disease_cause ,Real-Time Polymerase Chain Reaction ,Receptor, Angiotensin, Type 2 ,Retina ,Article ,Renin-Angiotensin System ,Cellular and Molecular Neuroscience ,Mice ,Renin–angiotensin system ,medicine ,Animals ,Humans ,RNA, Messenger ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,chemistry.chemical_classification ,Reactive oxygen species ,Sulfonamides ,Receptors, Angiotensin ,Chemistry ,NF-kappa B ,Angiotensin II ,Sensory Systems ,Cell biology ,Mice, Inbred C57BL ,Ophthalmology ,medicine.anatomical_structure ,Gene Expression Regulation ,Cytokines ,sense organs ,Signal transduction ,Reactive Oxygen Species ,Oxidative stress - Abstract
The renin-angiotensin system (RAS) plays a vital role in cardiovascular physiology and body homeostasis. In addition to circulating RAS, a local RAS exists in the retina. Dysfunction of local RAS, resulting in increased levels of Angiotensin II (Ang II) and activation of AT1R-mediated signaling pathways, contributes to tissue pathophysiology and end-organ damage. Activation of AT2R on other hand is known to counteract the effects of AT1R activation and produce anti-inflammatory and anti-oxidative effects. We examined the expression of angiotensin receptors in the retina by using transgenic dual reporter mice and by real-time RT-PCR. We further evaluated the effects of C21, a selective agonist of AT2R, in reducing Ang II, lipopolysaccharide (LPS) and hydrogen peroxide induced oxidative stress and inflammatory responses in cultured human ARPE-19 cells. We showed that both AT1Ra and AT2R positive cells are detected in different cell types of the eye, including the RPE/choroid complex, ciliary body/iris, and neural retina. AT1Ra is more abundantly expressed than AT2R in mouse retina, consistent with previous reports. In the neural retina, AT1Ra are also detected in photoreceptors whereas AT2R are mostly expressed in the inner retinal neurons and RGCs. In cultured human RPE cells, activation of AT2R with C21 significantly blocked Ang II, LPS and hydrogen peroxide -induced NF-κB activation and inflammatory cytokine expression; Ang II and hydrogen peroxide-induced reactive oxygen species (ROS) production and MG132-induced apoptosis, comparable to the effects of Angiotensin-(1–7) (Ang-(1–7)), another protective component of the RAS, although C21 is more potent in reducing some of the effects induced by Ang II, whereas Ang-(1–7) is more effective in reducing some of the LPS and hydrogen peroxide-induced effects. These results suggest that activation of AT2R may represent a new therapeutic approach for retinal diseases.
- Published
- 2019
39. Anti-fibrotic mechanisms of angiotensin AT
- Author
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Colin, Sumners, Antonio Augusto, Peluso, Andreas Houe, Haugaard, Jesper Bork, Bertelsen, and Ulrike Muscha, Steckelings
- Subjects
Heart Diseases ,Animals ,Humans ,Kidney Diseases ,Fibrosis ,Receptor, Angiotensin, Type 2 - Abstract
The angiotensin AT
- Published
- 2018
40. ANGIOTENSIN AT2 RECEPTORS IN THE NUCLEUS OF THE SOLITARY TRACT REDUCE BLOOD PRESSURE VIA INHIBITION OF GABA SIGNALING
- Author
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Mazher Mohammed, Eric G. Krause, Annette D. de Kloet, Karen A. Scott, Khalid Elsaafien, Dominique Johnson, and Colin Sumners
- Subjects
medicine.medical_specialty ,Physiology ,business.industry ,Solitary tract ,Endocrinology ,Blood pressure ,medicine.anatomical_structure ,Internal medicine ,Renin–angiotensin system ,Internal Medicine ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Receptor ,Nucleus - Published
- 2021
41. Adenovirus-Mediated Angiotensin II Type 2 Receptor Overexpression Inhibits Tumor Growth of Prostate Cancer In Vivo
- Author
-
Dongsheng Gu, Nana Pei, Hongyan Du, Xinglu Chen, Andrew Li, Weiwang Gu, Colin Sumners, Jie Luo, Feilong Jie, Yanling Zhang, Hongwei Li, Baihong Chen, and Jinlong Li
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,medicine.disease_cause ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,DU145 ,In vivo ,Prostate ,medicine ,Adenovirus ,business.industry ,apoptosis ,Cancer ,AT2R ,prostate cancer ,medicine.disease ,Angiotensin II ,tumor growth ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,Carcinogenesis ,business ,Research Paper - Abstract
The renin-angiotensin system (RAS) plays important roles in tumorigenesis and is involved with several hallmarks of cancer. Evidence shows that angiotensin II (AngII) type 1 receptor (AT1R) blockers may be associated with improved outcome in prostate cancer patients. Furthermore, our previous studies indicate that increased expression of Ang II type 2 receptor (AT2R) alone induced apoptosis in human prostate cancer lines, an effect that did not require Ang II. This study aimed to investigate the effects of AT2R on tumor growth in vivo and we hypothesized that AT2R over-expression would inhibit proliferation and induce apoptosis in vivo. Human prostate cancer DU145 xenograft mouse model was used to assess the effect of AT2R on tumor growth in vivo. Mice bearing a palpable tumor were chosen and divided randomly into three treatment groups: AT2R, GFP, and PBS. Then we directly injected into the xenograft tumors of the mice every three days with recombinant adenoviruses encoding AT2R (Ad5-CMV-AT2R-EGFP), EGFP (Ad5-CMV-EGFP) and PBS, respectively. The tumor sizes of the tumor bearing mice were then measured. Immunohistochemical Ki-67 staining and TUNEL assay were performed to examine the inhibitory effect of AT2R on tumor cell proliferation. The results showed that AT2R overexpression can inhibit tumor growth of prostate cancer in vivo by inhibiting proliferation and inducing apoptosis of tumor cells. GADD45A is involved in the AT2R-induced antitumor activity. This suggests that AT2R is a potentially useful gene for prostate gene therapy.
- Published
- 2016
42. Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts
- Author
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Haifa Zheng, Andrew Li, Michael J. Katovich, Wenjin Wei, Hongwei Li, Hongyan Du, Colin Sumners, Yanfei Qi, Yanling Zhang, Nana Pei, Jinlong Li, Yi Zhang, Renqiang Wan, Xinglu Chen, and Baihong Chen
- Subjects
Vascular Endothelial Growth Factor A ,0301 basic medicine ,Cancer Research ,MAP Kinase Signaling System ,medicine.drug_class ,Angiogenesis ,Angiogenesis Inhibitors ,Proto-Oncogene Mas ,Neovascularization ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptor ,Cell Proliferation ,Nasopharyngeal Carcinoma ,Neovascularization, Pathologic ,Chemistry ,Cell growth ,Carcinoma ,Membrane Proteins ,Nasopharyngeal Neoplasms ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Receptor antagonist ,Xenograft Model Antitumor Assays ,Peptide Fragments ,Tumor Burden ,Disease Models, Animal ,Receptors, Vascular Endothelial Growth Factor ,030104 developmental biology ,Oncology ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Adenocarcinoma ,Female ,Angiotensin I ,medicine.symptom - Abstract
Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, heptapeptide hormone acting through the Mas receptor (MasR), with antiproliferative and antiangiogenic properties. Recent studies have shown that Ang-(1-7) has an antiproliferative action on lung adenocarcinoma cells and prostate cancer cells. In this study, we report that MasR levels were significantly upregulated in nasopharyngeal carcinoma (NPC) specimens and NPC cell lines. Viral vector–mediated expression of Ang-(1-7) dramatically suppressed NPC cell proliferation and migration in vitro. These effects were completely blocked by the specific Ang-(1-7) receptor antagonist A-779, suggesting that they are mediated by the Ang-(1-7) receptor Mas. In this study, Ang-(1-7) not only caused a significant reduction in the growth of human nasopharyngeal xenografts, but also markedly decreased vessel density, suggesting that the heptapeptide inhibits angiogenesis to reduce tumor size. Mechanistic investigations revealed that Ang-(1-7) inhibited the expression of the proangiogenic factors VEGF and PlGF. Taken together, the data suggest that upregulation of MasR could be used as a diagnostic marker of NPC and Ang-(1-7) may be a novel therapeutic agent for nasopharyngeal cancer therapy because it exerts significant antiangiogenic activity. Mol Cancer Ther; 15(1); 37–47. ©2015 AACR.
- Published
- 2016
43. Modulating of ocular inflammation with macrophage migration inhibitory factor is associated with notch signalling in experimental autoimmune uveitis
- Author
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Qiuhong Li, Hongwei Li, Changwei Zheng, Bo Lei, Yingying Mao, Colin Sumners, Hongxia Yang, Peizeng Yang, Shijie Zheng, and Zihe Chen
- Subjects
Male ,0301 basic medicine ,CD74 ,Genetic Vectors ,Immunology ,Notch signaling pathway ,Enzyme-Linked Immunosorbent Assay ,Mice, Inbred Strains ,Inflammation ,Biology ,Real-Time Polymerase Chain Reaction ,Retina ,Autoimmune Diseases ,Proinflammatory cytokine ,Uveitis ,Mice ,03 medical and health sciences ,Electroretinography ,medicine ,Animals ,Immunology and Allergy ,Eye Proteins ,Receptor ,Macrophage Migration-Inhibitory Factors ,Receptors, Notch ,Original Articles ,Dependovirus ,Th1 Cells ,medicine.disease ,eye diseases ,Intramolecular Oxidoreductases ,Retinol-Binding Proteins ,Disease Models, Animal ,030104 developmental biology ,Cytokines ,Th17 Cells ,Female ,Macrophage migration inhibitory factor ,sense organs ,medicine.symptom ,Signal transduction ,Signal Transduction - Abstract
Summary The aim of this study was to examine whether macrophage migration inhibitory factor (MIF) could exaggerate inflammatory response in a mouse model of experimental autoimmune uveitis (EAU) and to explore the underlying mechanism. Mutant serotype 8 adeno-associated virus (AAV8) (Y733F)-chicken β-actin (CBA)-MIF or AAV8 (Y733F)-CBA-enhanced green fluorescent protein (eGFP) vector was delivered subretinally into B10.RIII mice, respectively. Three weeks after vector delivery, EAU was induced with a subcutaneous injection of a mixture of interphotoreceptor retinoid binding protein (IRBP) peptide with CFA. The levels of proinflammatory cytokines were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Retinal function was evaluated with electroretinography (ERG). We found that the expression of MIF and its two receptors CD74 and CD44 was increased in the EAU mouse retina. Compared to AAV8.CBA.eGFP-injected and untreated EAU mice, the level of proinflammatory cytokines, the expression of Notch1, Notch4, delta-like ligand 4 (Dll4), Notch receptor intracellular domain (NICD) and hairy enhancer of split-1 (Hes-1) increased, but the ERG a- and b-wave amplitudes decreased in AAV8.CBA.MIF-injected EAU mice. The Notch inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) reduced the expression of NICD, Hes-1 and proinflammatory cytokines. Further, a MIF antagonist ISO-1 attenuated intraocular inflammation, and inhibited the differentiation of T helper type 1 (Th1) and Th17 in EAU mice. We demonstrated that over-expression of MIF exaggerated ocular inflammation, which was associated with the activation of the Notch signalling. The expression of both MIF and its receptors are elevated in EAU mice. Over-expression of MIF exaggerates ocular inflammation, and this exaggerated inflammation is associated with the activation of the Notch signalling and Notch pathway. Our data suggest that the MIF–Notch axis may play an important role in the pathogenesis of EAU. Both the MIF signalling pathways may be promising targets for developing novel therapeutic interventions for uveitis.
- Published
- 2015
44. Angiotensin AT2 receptors in the solitary tract nucleus lower blood pressure via inhibition of GABA signaling
- Author
-
Mazher Mohammed, Eric G. Krause, Annette D. de Kloet, Karen A. Scott, Dominique Johnson, Charles J. Frazier, Wanhui Sheng, Colin Sumners, and Scott W Harden
- Subjects
medicine.medical_specialty ,Endocrinology ,Chemistry ,Lower blood pressure ,Internal medicine ,Renin–angiotensin system ,Genetics ,medicine ,Receptor ,Molecular Biology ,Biochemistry ,Solitary tract nucleus ,Biotechnology - Published
- 2020
45. Identification of protein phosphatase involvement in the AT 2 receptor-induced activation of endothelial nitric oxide synthase
- Author
-
Michael Bader, Jesper Bork Bertelsen, Pernille B. Lærkegaard Hansen, Robson A.S. Santos, Colin Sumners, Tenna Pavia Mortsensen, Kenneth Andersen, A. Augusto Peluso, and Ulrike Muscha Steckelings
- Subjects
0301 basic medicine ,Phosphatase ,Protein tyrosine phosphatase ,Thiophenes ,030204 cardiovascular system & hematology ,Nitric oxide ,Dephosphorylation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Enos ,Humans ,Phosphorylation ,Protein kinase B ,Sodium orthovanadate ,Cells, Cultured ,Sulfonamides ,biology ,Nitric Oxide Synthase Type III/metabolism ,General Medicine ,Protein-Serine-Threonine Kinases/metabolism ,biology.organism_classification ,Molecular biology ,Receptor, Angiotensin, Type 2/agonists ,Protein-Tyrosine Kinases/metabolism ,Enzyme Activation ,030104 developmental biology ,chemistry - Abstract
The Angiotensin II type 2 receptor (AT 2R) promotes vasodilation by nitric oxide (NO) release from endothelial cells. However, the mechanisms underlying the AT 2R-induced stimulation of endothelial NO synthase (eNOS) is still not completely understood. Therefore, we investigated whether in addition to the known AT 2R-mediated phosphorylation of eNOS at Ser 1177, activation of phosphatases and dephosphorylation of eNOS at Tyr 657 and Thr 495 are also involved. Human aortic endothelial cells (HAEC) were stimulated with the AT 2R-agonist Compound 21 (C21) (1 μM) in the presence or absence of either PD123319 (10 μM; AT 2R antagonist), L-NG-Nitroarginine methyl ester (L-NAME) (10 μM; eNOS inhibitor), MK-2206 (100 nM; protein kinase B (Akt) inhibitor) sodium fluoride (NaF) (1 nM; serine/threonine phosphatase inhibitor) or sodium orthovanadate (Na 3VO 4) (10 nM; tyrosine phosphatase inhibitor). NO release was estimated by quantifying 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM) fluorescence. The phosphorylation status of activating (eNOS-Ser 1177) or inhibitory eNOS residues (eNOS-Tyr 657, eNOS-Thr 495) was determined by Western blotting. Phosphorylation of Akt at Ser 473 was measured to estimate Akt activity. AT 2R stimulation significantly increased NO release from HAEC, which was blocked by PD123319, L-NAME and both phosphatase inhibitors. Intracellular calcium transients were not changed by C21. AT 2R stimulation resulted in phosphorylation of eNOS-Ser 1177 and dephosphorylation of eNOS-Tyr 657 and eNOS-Thr 495. Phosphorylation at eNOS-Ser 1177 was prevented by inhibition of Akt with MK-2206. From these data, we conclude that AT 2R stimulation in human endothelial cells increases eNOS activity through phosphorylation of activating eNOS residues (eNOS-Ser 1177) by Akt, and through dephosphorylation of inactivating eNOS residues (eNOS-Tyr 657, eNOS-Thr 495) by serine/threonine and tyrosine phosphatases, thus increasing NO release.
- Published
- 2018
46. Butyrate regulates inflammatory cytokine expression without affecting oxidative respiration in primary astrocytes from spontaneously hypertensive rats
- Author
-
Wendi L. Malphurs, Colin Sumners, Jasenka Zubcevic, Jordan T. Schmidt, Christopher J. Martyniuk, Vermali Rodriguez, Niousha Ahmari, and Tao Yang
- Subjects
Male ,Central Nervous System ,medicine.medical_specialty ,microbial metabolites ,Physiology ,Cell Respiration ,Immunology ,Blood Pressure ,Butyrate ,030204 cardiovascular system & hematology ,Mitochondrion ,medicine.disease_cause ,Oxidative Phosphorylation ,Proinflammatory cytokine ,Rats, Sprague-Dawley ,03 medical and health sciences ,Hydroxybutyrate Dehydrogenase ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Rats, Inbred SHR ,medicine ,Metabolism and Regulation ,Animals ,Neuroinflammation ,Cells, Cultured ,Chemokine CCL2 ,Original Research ,biology ,Chemistry ,Neurogenic hypertension ,butyrate ,Rats ,glial cells ,Toll-Like Receptor 4 ,Butyrates ,Monocarboxylate transporter 1 ,medicine.anatomical_structure ,Endocrinology ,Astrocytes ,Hypertension ,biology.protein ,Female ,neurogenic hypertension ,030217 neurology & neurosurgery ,Oxidative stress ,Astrocyte - Abstract
Neurons and glia exhibit metabolic imbalances in hypertensive animal models, and loss of metabolic homeostasis can lead to neuroinflammation and oxidative stress. The objective of this study was to determine the effects of the microbial metabolite butyrate on mitochondrial bioenergetics and inflammatory markers in mixed brainstem and hypothalamic primary cultures of astrocytes between normotensive (Sprague‐Dawley, S‐D) and spontaneously hypertensive (SHR) rats. Bioenergetics of mitochondria in astrocytes from normotensive S‐D rats were modified with butyrate, but this was not the case in astrocytes derived from SHR, suggesting aberrant mitochondrial function. Transcripts related to oxidative stress, butyrate transporters, butyrate metabolism, and neuroinflammation were quantified in astrocyte cultures treated with butyrate at 0, 200, 600, and 1000 μmol/L. Butyrate decreased catalase and monocarboxylate transporter 1 mRNA in astrocytes of S‐D rats but not in the SHR. Moreover, while butyrate did not directly regulate the expression of 3‐hydroxybutyrate dehydrogenase 1 and 2 in astrocytes of either strain, the expression levels for these transcripts in untreated cultures were lower in the SHR compared to S‐D. We observed higher levels of specific inflammatory cytokines in astrocytes of SHR, and treatment with butyrate decreased expression of Ccl2 and Tlr4 in SHR astrocytes only. Conversely, butyrate treatment increased expression of tumor necrosis factor in astrocytes from SHR but not from the S‐D rats. This study improves our understanding of the role of microbial metabolites in regulating astrocyte function, and provides support that butyrate differentially regulates both the bioenergetics and transcripts related to neuroinflammation in astrocytes from SHR versus S‐D rats.
- Published
- 2018
47. Neuroprotection via AT
- Author
-
Douglas M, Bennion, U Muscha, Steckelings, and Colin, Sumners
- Subjects
Stroke ,Neuroprotective Agents ,Blood-Brain Barrier ,Risk Factors ,Animals ,Humans ,Molecular Targeted Therapy ,Receptor, Angiotensin, Type 2 ,Neuroprotection - Abstract
Stroke is a devastating disease that afflicts millions of people each year worldwide. Ischemic stroke, which accounts for ~88% of cases, occurs when blood supply to the brain is decreased, often because of thromboembolism or atherosclerotic occlusion. This deprives the brain of oxygen and nutrients, causing immediate, irreversible necrosis within the core of the ischemic area, but more delayed and potentially reversible neuronal damage in the surrounding brain tissue, the penumbra. The only currently approved therapies for ischemic stroke, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) and the endovascular clot retrieval/destruction processes, are aimed at restoring blood flow to the infarcted area, but are only available for a minority of patients and are not able in most cases to completely restore neurological deficits. Consequently, there remains a need for agents that will protect neurones against death following ischemic stroke. Here, we evaluate angiotensin II (Ang II) type 2 (AT
- Published
- 2018
48. Protective effects of the angiotensin II AT
- Author
-
Douglas M, Bennion, Chad H, Jones, Alex N, Dang, Jacob, Isenberg, Justin T, Graham, Lena, Lindblad, Oliver, Domenig, Michael F, Waters, Marko, Poglitsch, Colin, Sumners, and Ulrike Muscha, Steckelings
- Subjects
Male ,Sulfonamides ,Drug Administration Routes ,Brain ,Cerebral Infarction ,Thiophenes ,Receptor, Angiotensin, Type 2 ,Brain Ischemia ,Rats, Sprague-Dawley ,Stroke ,Nasal Mucosa ,Drug Delivery Systems ,Neuroprotective Agents ,Animals ,Humans - Abstract
Significant neuroprotective effects of angiotensin II type 2 (AT
- Published
- 2018
49. Cellular and Molecular Biology of the Renin-Angiotensin System
- Author
-
Ernesto Schiffrin, Colin Sumners, and Štefan Zorad
- Subjects
Angiotensin receptor ,Transgene ,Renin–angiotensin system ,Biology ,Molecular biology - Abstract
"Cellular and Molecular Biology of the Renin-Angiotensin System" provides an update of the state-of-the-art cellular and molecular aspects of the renin-angiotensin system. The book presents detailed analyses on each component of this system, including future directions. Topics range from the angiotensin II receptor subtypes to processing of renin to the use of transgenic animal models for studying the role of this system in hypertension.
- Published
- 2018
50. Identification of protein phosphatase involvement in the AT
- Author
-
A Augusto, Peluso, Jesper Bork, Bertelsen, Kenneth, Andersen, Tenna Pavia, Mortsensen, Pernille B, Hansen, Colin, Sumners, Michael, Bader, Robson A, Santos, and Ulrike Muscha, Steckelings
- Subjects
Enzyme Activation ,Sulfonamides ,Nitric Oxide Synthase Type III ,Humans ,Thiophenes ,Phosphorylation ,Protein Serine-Threonine Kinases ,Protein-Tyrosine Kinases ,Receptor, Angiotensin, Type 2 ,Cells, Cultured - Abstract
The Angiotensin II type 2 receptor (AT
- Published
- 2017
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