68 results on '"Spiekerkoetter E"'
Search Results
2. Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.
- Author
-
DeBose-Scarlett E, Ressler AK, Gallione CJ, Sapisochin Cantis G, Friday C, Weinsheimer S, Schimmel K, Spiekerkoetter E, Kim H, Gossage JR, Faughnan ME, and Marchuk DA
- Subjects
- Humans, Female, Male, Loss of Heterozygosity genetics, Adult, Activin Receptors, Type II genetics, Germ-Line Mutation, Phenotype, Middle Aged, Telangiectasia, Hereditary Hemorrhagic genetics, Telangiectasia, Hereditary Hemorrhagic pathology, Arteriovenous Malformations genetics, Arteriovenous Malformations pathology, Alleles, Mutation
- Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs. HHT is caused by inheritance of a loss of function mutation in one of three genes. Although individuals with HHT are haploinsufficient for one of these genes throughout their entire body, rather than exhibiting a systemic vascular phenotype, vascular malformations occur as focal lesions in discrete anatomic locations. The inconsistency between genotype and phenotype has provoked debate over whether haploinsufficiency or a different mechanism gives rise to the vascular malformations. We previously showed that HHT-associated skin telangiectases develop by a two-hit mutation mechanism in an HHT gene. However, somatic mutations were identified in only half of the telangiectases, raising the question whether a second-hit somatic mutation is a necessary (required) event in HHT pathogenesis. Here, we show that another mechanism for the second hit is loss of heterozygosity across the chromosome bearing the germline mutation. Secondly, we investigate the two-hit mutation mechanism for internal organ AVMs, the source of much of the morbidity of HHT. Here, we identified somatic molecular genetic events in eight liver telangiectases, including point mutations and a loss of heterozygosity event. We also identified somatic mutations in one pulmonary AVM and two brain AVMs, confirming that mucocutaneous and internal organ vascular malformations undergo the same molecular mechanisms. Together, these data argue that bi-allelic loss of function in an HHT gene is a required event in the pathogenesis of HHT-associated vascular malformations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
- Full Text
- View/download PDF
3. Tricuspid annular plane systolic excursion in pulmonary hypertension-Moving beyond the sector plane.
- Author
-
Ichimura K, Celestin BE, Bagherzadeh SP, Zamanian RT, Salerno M, Spiekerkoetter E, and Haddad F
- Abstract
Tricuspid annular plane systolic excursion (TAPSE) is usually measured with M-mode using sector line, however, this may not align with the anatomical shortening of the right ventricular (RV). In this study, we compared the different methods to measure TAPSE using three different reference lines (sector line, anatomical line, and apico-annular line). We included 148 patients diagnosed with pulmonary arterial hypertension (PAH) who underwent TTE and right heart catheterization within 2 weeks of each other. TAPSE was measured by M-mode (sector, anatomical), 2D (sector, anatomical), or as tricuspid apico-annular displacement (TAAD). Agreement between measures was assessed using coefficient of variation (COV), Spearman's correlation, and Bland-Altman analysis. Receiver-operating characteristics and Kaplan-Meier analysis were used to explore associations with the combined outcome of death or lung transplantation at 5 years. There was a good concordance between anatomical and sector M-mode with a COV of 15.5 ± 1.6% and a bias of -0.6 ± 3.2 mm. In contrast, anatomical M-mode TAPSE and TAAD differed significantly with the mean difference of 3.3 ± 3.8 mm (COV 30.5 ± 6.1%; p < 0.0001). Among the different 2D methods, anatomical 2D agreed well with anatomical M-mode TAPSE (COV of 11.8 ± 2.0%; r = 0.89; p < 0.0001). Among the five methods, TADD had the strongest association with the combined endpoint of death or transplantation at 5 years (C-statistic 0.64, 95% confidence interval [CI] 0.57-0.71). We concluded that different measures of TAPSE are not interchangeable., Competing Interests: Dr. Haddad reports research grants from Actelion Pharmaceuticals, a Janssen Company of Johnson & Johnson, focused on computational approaches for the diagnosis and monitoring of pulmonary hypertension. The other authors report no conflicts relevant to this study., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)
- Published
- 2024
- Full Text
- View/download PDF
4. 3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension.
- Author
-
Ichimura K, Boehm M, Andruska AM, Zhang F, Schimmel K, Bonham S, Kabiri A, Kheyfets VO, Ichimura S, Reddy S, Mao Y, Zhang T, Wang GX, Santana EJ, Tian X, Essafri I, Vinh R, Tian W, Nicolls MR, Yajima S, Shudo Y, MacArthur JW, Woo YJ, Metzger RJ, and Spiekerkoetter E
- Subjects
- Animals, Humans, Mice, Male, Heart Ventricles physiopathology, Heart Ventricles diagnostic imaging, Heart Ventricles pathology, Microvessels physiopathology, Microvessels diagnostic imaging, Microvessels pathology, Vascular Remodeling, Pulmonary Artery physiopathology, Pulmonary Artery diagnostic imaging, Pulmonary Artery pathology, Ventricular Dysfunction, Right physiopathology, Ventricular Dysfunction, Right etiology, Ventricular Dysfunction, Right diagnostic imaging, Ventricular Function, Right, Ventricular Remodeling, Disease Models, Animal, Myocytes, Cardiac pathology, Imaging, Three-Dimensional, Hypertension, Pulmonary physiopathology, Hypertension, Pulmonary diagnostic imaging, Hypertension, Pulmonary etiology, Hypertension, Pulmonary pathology, Mice, Inbred C57BL
- Abstract
Background: Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure., Methods: Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function., Results: Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments., Conclusions: 3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction., Competing Interests: Disclosures None.
- Published
- 2024
- Full Text
- View/download PDF
5. Cardiorenal Syndrome in Right Heart Failure Due to Pulmonary Arterial Hypertension-The Right Ventricle as a Therapeutic Target to Improve Renal Function.
- Author
-
Ichimura K, Gross A, Mathew RO, Salman L, Reddy S, Spiekerkoetter E, and Sidhu MS
- Abstract
Cardiorenal syndrome (CRS) due to right ventricular (RV) failure is a disease entity emerging as a key indicator of morbidity and mortality. The multifactorial aspects of CRS and the left-right ventricular interdependence complicate the link between RV failure and renal function. RV failure has a direct pathophysiological link to renal dysfunction by leading to systemic venous congestion in certain circumstances and low cardiac output in other situations, both leading to impaired renal perfusion. Indeed, renal dysfunction is known to be an independent predictor of mortality in patients with pulmonary arterial hypertension (PAH) and RV failure. Thus, it is important to further understand the interaction between the RV and renal function. RV adaptation is critical to long-term survival in patients with PAH. The RV is also known for its remarkable capacity to recover once the aggravating factor is addressed or mitigated. However, less is known about the renal potential for recovery following the resolution of chronic RV failure. In this review, we provide an overview of the intricate relationship between RV dysfunction and the subsequent development of CRS, with a particular emphasis on PAH. Additionally, we summarize potential RV-targeted therapies and their potential beneficial impact on renal function., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2024
- Full Text
- View/download PDF
6. MicroRNA-34a-Dependent Attenuation of Angiogenesis in Right Ventricular Failure.
- Author
-
Reddy S, Hu DQ, Zhao M, Ichimura S, Barnes EA, Cornfield DN, Alejandre Alcázar MA, Spiekerkoetter E, Fajardo G, and Bernstein D
- Subjects
- Child, Humans, Mice, Animals, Vascular Endothelial Growth Factor A metabolism, Endothelial Cells metabolism, Angiogenesis, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Hypertrophy, Right Ventricular, Myocytes, Cardiac metabolism, Microvascular Rarefaction metabolism, Heart Failure metabolism, MicroRNAs genetics, MicroRNAs metabolism, Heart Defects, Congenital metabolism
- Abstract
Background: The right ventricle (RV) is at risk in patients with complex congenital heart disease involving right-sided obstructive lesions. We have shown that capillary rarefaction occurs early in the pressure-loaded RV. Here we test the hypothesis that microRNA (miR)-34a, which is induced in RV hypertrophy and RV failure (RVF), blocks the hypoxia-inducible factor-1α-vascular endothelial growth factor (VEGF) axis, leading to the attenuated angiogenic response and increased susceptibility to RV failure., Methods and Results: Mice underwent pulmonary artery banding to induce RV hypertrophy and RVF. Capillary rarefaction occurred immediately. Although hypoxia-inducible factor-1α expression increased (0.12±0.01 versus 0.22±0.03, P =0.05), VEGF expression decreased (0.61±0.03 versus 0.22±0.05, P =0.01). miR-34a expression was most upregulated in fibroblasts (4-fold), but also in cardiomyocytes and endothelial cells (2-fold). Overexpression of miR-34a in endothelial cells increased cell senescence (10±3% versus 22±2%, P <0.05) by suppressing sirtulin 1 expression, and decreased tube formation by 50% via suppression of hypoxia-inducible factor-1α, VEGF A, VEGF B, and VEGF receptor 2. miR-34a was induced by stretch, transforming growth factor-β1, adrenergic stimulation, and hypoxia in cardiac fibroblasts and cardiomyocytes. In mice with RVF, locked nucleic acid-antimiR-34a improved RV shortening fraction and survival half-time and restored capillarity and VEGF expression. In children with congenital heart disease-related RVF, RV capillarity was decreased and miR-34a increased 5-fold., Conclusions: In summary, miR-34a from fibroblasts, cardiomyocytes, and endothelial cells mediates capillary rarefaction by suppressing the hypoxia-inducible factor-1α-VEGF axis in RV hypertrophy/RVF, raising the potential for anti-miR-34a therapeutics in patients with at-risk RVs.
- Published
- 2024
- Full Text
- View/download PDF
7. Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs.
- Author
-
Zhao L, Cunningham CM, Andruska AM, Schimmel K, Ali MK, Kim D, Gu S, Chang JL, Spiekerkoetter E, and Nicolls MR
- Subjects
- Humans, Rats, Animals, Bacteria, Lung microbiology, Lactobacillales, Microbiota genetics
- Abstract
The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of healthy Fischer 344 rats across their lifespan. Microbial community profiling data were extracted and integrated with host transcriptomic data from the Sequencing Quality Control consortium. Unsupervised machine learning, correlation, taxonomic diversity and abundance analyses were performed to determine and characterize the rat microbial biogeography and identify four intertissue microbial heterogeneity patterns (P1-P4). We found that the 11 body habitats harbored a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundance progressively declined in lungs from breastfed newborn to adolescence/adult, and was below detectable levels in elderly rats. Bioinformatics analyses indicate that the abundance of LAB may be modulated by the lung-immune axis. The presence and levels of LAB in lungs were further evaluated by PCR in two validation datasets. The lung, testes, thymus, kidney, adrenal and muscle niches were found to have age-dependent alterations in microbial abundance. The 357 microbial signatures were positively correlated with host genes in cell proliferation (P1), DNA damage repair (P2) and DNA transcription (P3). Our study established a link between the metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures could be useful for microbiome therapeutic approaches to human health and life quality enhancement., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2024
- Full Text
- View/download PDF
8. Characterizing the Spatiotemporal Transcriptomic Response of the Right Ventricle to Acute Pressure Overload.
- Author
-
Kheyfets VO, Kumar S, Heerdt PM, Ichimura K, Brown RD, Lucero M, Essafri I, Williams S, Stenmark KR, and Spiekerkoetter E
- Subjects
- Rats, Animals, Heart Ventricles metabolism, Transcriptome, Gene Expression Profiling, Disease Models, Animal, Ventricular Remodeling, Hypertension, Pulmonary metabolism, Pulmonary Embolism
- Abstract
This study analyzed microarray data of right ventricular (RV) tissue from rats exposed to pulmonary embolism to understand the initial dynamic transcriptional response to mechanical stress and compare it with experimental pulmonary hypertension (PH) models. The dataset included samples harvested from 55 rats at 11 different time points or RV locations. We performed principal component analysis (PCA) to explore clusters based on spatiotemporal gene expression. Relevant pathways were identified from fast gene set enrichment analysis using PCA coefficients. The RV transcriptomic signature was measured over several time points, ranging from hours to weeks after an acute increase in mechanical stress, and was found to be highly dependent on the severity of the initial insult. Pathways enriched in the RV outflow tracts of rats at 6 weeks after severe PE share many commonalities with experimental PH models, but the transcriptomic signature at the RV apex resembles control tissue. The severity of the initial pressure overload determines the trajectory of the transcriptomic response independent of the final afterload, but this depends on the location where the tissue is biopsied. Chronic RV pressure overload due to PH appears to progress toward similar transcriptomic endpoints.
- Published
- 2023
- Full Text
- View/download PDF
9. Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs.
- Author
-
Zhao L, Cunningham CM, Andruska AM, Schimmel K, Ali MK, Kim D, Gu S, Chang JL, Spiekerkoetter E, and Nicolls MR
- Abstract
The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined a multi-tissue full lifespan microbial biogeography for healthy Fischer 344 rats. Microbial community profiling data was extracted and integrated with host transcriptomic data from the Sequencing Quality Control (SEQC) consortium. Unsupervised machine learning, Spearman's correlation, taxonomic diversity, and abundance analyses were performed to determine and characterize the rat microbial biogeography and the identification of four inter-tissue microbial heterogeneity patterns (P1-P4). The 11 body habitats harbor a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundances progressively declined in lungs from breastfeed newborn to adolescence/adult and was below detectable levels in elderly rats. LAB's presence and levels in lungs were further evaluated by PCR in the two validation datasets. The lung, testes, thymus, kidney, adrenal, and muscle niches were found to have age-dependent alterations in microbial abundance. P1 is dominated by lung samples. P2 contains the largest sample size and is enriched for environmental species. Liver and muscle samples were mostly classified into P3. Archaea species were exclusively enriched in P4. The 357 pattern-specific microbial signatures were positively correlated with host genes in cell migration and proliferation (P1), DNA damage repair and synaptic transmissions (P2), as well as DNA transcription and cell cycle in P3. Our study established a link between metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures would be useful for microbiome therapeutic approaches to human health and good quality of life.
- Published
- 2023
- Full Text
- View/download PDF
10. Repetitive schistosoma exposure causes perivascular lung fibrosis and persistent pulmonary hypertension.
- Author
-
Kumar R, Lee MH, Kassa B, Fonseca Balladares DC, Mickael C, Sanders L, Andruska A, Kumar M, Spiekerkoetter E, Bandeira A, Stenmark KR, Tuder RM, and Graham BB
- Subjects
- Humans, Animals, Mice, Schistosoma mansoni, Lung pathology, Fibrosis, Hypertension, Pulmonary etiology, Pulmonary Fibrosis complications, Schistosomiasis complications, Schistosomiasis pathology
- Abstract
Background: Pulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite antihelminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition., Methods: Following intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis., Results: Following intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7-14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition., Conclusions: Repeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease., (© 2023 The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
11. Novel left ventricular mechanical index in pulmonary arterial hypertension.
- Author
-
Ichimura K, Santana EJ, Kuznetsova T, Cauwenberghs N, Sabovčik F, Chun L, Francisco NLC, Kheyfets VO, Salerno M, Zamanian RT, Spiekerkoetter E, and Haddad F
- Abstract
Ventricular interdependence plays an important role in pulmonary arterial hypertension (PAH). It can decrease left ventricular (LV) longitudinal strain (LVLS) and lead to a leftward displacement ("transverse shortening") of the interventricular septum (sTS). For this study, we hypothesized the ratio of LVLS/sTS would be a sensitive marker of systolic ventricular interactions in PAH. In a cross-sectional cohort of patients with PAH ( n = 57) and matched controls ( n = 57), we quantified LVLS and septal TS in the amplitude and time domain. We then characterized LV phenotypes using upset plots, ventricular interactions using network analysis, and longitudinal analysis in a representative cohort of 45 patients. We also measured LV metrics in mice subjected to pulmonary arterial banding (PAB) using a 7 T magnetic resonance imaging at baseline, Week 1, and Week 7 post-PAB ( N = 9). Patients with PAH had significantly reduced absolute LVLS (15.4 ± 3.4 vs. 20.1 ± 2.3%, p < 0.0001), higher sTS (53.0 ± 12.2 vs. 28.0 ± 6.2%, p < 0.0001) and lower LVLS/sTS (0.30 ± 0.09 vs. 0.75 ± 0.16, p < 0.0001) compared to controls. Reduced LVLS/sTS was observed in 89.5% of patients, while diastolic dysfunction, impaired LVLS (<16%), and LV atrophy were observed in 73.7%, 52.6%, and 15.8%, respectively. In the longitudinal cohort, changes in LVLS/sTS were closely associated with changes in N-terminal pro B-type natriuretic peptide ( r = 0.73, p < 0.0001) as well as survival. Mice subjected to PAB showed significant RV systolic dysfunction and decreased LVLS/sTS compared to sham animals. We conclude that in PAH, LVLV/sTS is a simple ratio that can reflect ventricular systolic interactions., Competing Interests: Francois Haddad reports research grants from Actelion Pharmaceuticals, a Janssen Company of Johnson & Johnson focused on computational approaches for the diagnosis and monitoring of pulmonary hypertension. The other authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)
- Published
- 2023
- Full Text
- View/download PDF
12. The Human Respiratory Microbiome: Current Understandings and Future Directions.
- Author
-
Zhao L, Luo JL, Ali MK, Spiekerkoetter E, and Nicolls MR
- Subjects
- Humans, Lung microbiology, Asthma, Pulmonary Disease, Chronic Obstructive microbiology, Microbiota, Cystic Fibrosis microbiology
- Abstract
Microorganisms colonize the human body. The lungs and respiratory tract, previously believed to be sterile, harbor diverse microbial communities and the genomes of bacteria (bacteriome), viruses (virome), and fungi (mycobiome). Recent advances in amplicon and shotgun metagenomic sequencing technologies and data-analyzing methods have greatly aided the identification and characterization of microbial populations from airways. The respiratory microbiome has been shown to play roles in human health and disease and is an area of rapidly emerging interest in pulmonary medicine. In this review, we provide updated information in the field by focusing on four lung conditions, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis. We evaluate gut, oral, and upper airway microbiomes and how they contribute to lower airway flora. The discussion is followed by a systematic review of the lower airway microbiome in health and disease. We conclude with promising research avenues and implications for evolving therapeutics.
- Published
- 2023
- Full Text
- View/download PDF
13. The role of circular RNAs in pulmonary hypertension.
- Author
-
Ali MK, Schimmel K, Zhao L, Chen CK, Dua K, Nicolls MR, and Spiekerkoetter E
- Subjects
- Humans, RNA, Circular genetics, Vascular Remodeling genetics, Biomarkers metabolism, Hypertension, Pulmonary genetics, MicroRNAs genetics
- Abstract
Circular RNAs (circRNAs) are endogenous, covalently circularised, non-protein-coding RNAs generated from back-splicing. Most circRNAs are very stable, highly conserved, and expressed in a tissue-, cell- and developmental stage-specific manner. circRNAs play a significant role in various biological processes, such as regulation of gene expression and protein translation via sponging of microRNAs and binding with RNA-binding proteins. circRNAs have become a topic of great interest in research due to their close link with the development of various diseases. Their high stability, conservation and abundance in body fluids make them promising biomarkers for many diseases. A growing body of evidence suggests that aberrant expression of circRNAs and their targets plays a crucial role in pulmonary vascular remodelling and pulmonary arterial hypertension (group 1) as well as other forms (groups 3 and 4) of pulmonary hypertension (PH). Here we discuss the roles and molecular mechanisms of circRNAs in the pathogenesis of pulmonary vascular remodelling and PH. We also highlight the therapeutic and biomarker potential of circRNAs in PH., Competing Interests: Conflict of interest: The authors have no conflicts of interest to declare., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)
- Published
- 2022
- Full Text
- View/download PDF
14. Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant.
- Author
-
Heydarian M, Oak P, Zhang X, Kamgari N, Kindt A, Koschlig M, Pritzke T, Gonzalez-Rodriguez E, Förster K, Morty RE, Häfner F, Hübener C, Flemmer AW, Yildirim AO, Sudheendra D, Tian X, Petrera A, Kirsten H, Ahnert P, Morrell N, Desai TJ, Sucre J, Spiekerkoetter E, and Hilgendorff A
- Subjects
- Infant, Infant, Newborn, Humans, Mice, Animals, Infant, Premature, Lung, Mice, Transgenic, Risk Factors, Animals, Newborn, Vascular System Injuries complications, Vascular System Injuries pathology, Bronchopulmonary Dysplasia etiology, Hyperoxia complications, Hyperoxia metabolism, Hyperoxia pathology
- Abstract
Introduction: Chronic lung disease, that is, bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and develops as a consequence of the misguided formation of the gas-exchange area undergoing prenatal and postnatal injury. Subsequent vascular disease and its progression into pulmonary arterial hypertension critically determines long-term outcome in the BPD infant but lacks identification of early, disease-defining changes., Methods: We link impaired bone morphogenetic protein (BMP) signalling to the earliest onset of vascular pathology in the human preterm lung and delineate the specific effects of the most prevalent prenatal and postnatal clinical risk factors for lung injury mimicking clinically relevant conditions in a multilayered animal model using wild-type and transgenic neonatal mice., Results: We demonstrate (1) the significant reduction in BMP receptor 2 (BMPR2) expression at the onset of vascular pathology in the lung of preterm infants, later mirrored by reduced plasma BMP protein levels in infants with developing BPD, (2) the rapid impairment (and persistent change) of BMPR2 signalling on postnatal exposure to hyperoxia and mechanical ventilation, aggravated by prenatal cigarette smoke in a preclinical mouse model and (3) a link to defective alveolar septation and matrix remodelling through platelet derived growth factor-receptor alpha deficiency. In a treatment approach, we partially reversed vascular pathology by BMPR2-targeted treatment with FK506 in vitro and in vivo., Conclusion: We identified impaired BMP signalling as a hallmark of early vascular disease in the injured neonatal lung while outlining its promising potential as a future biomarker or therapeutic target in this growing, high-risk patient population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
- Full Text
- View/download PDF
15. Shunt-type plexiform lesions identified in the Sugen5416/hypoxia rat model of pulmonary arterial hypertension using synchrotron-based phase-contrast micro-CT.
- Author
-
van der Have O, Westöö C, Ahrné F, Tian X, Ichimura K, Dreier T, Norvik C, Kumar ME, Spiekerkoetter E, and Tran-Lundmark K
- Subjects
- Animals, Disease Models, Animal, Familial Primary Pulmonary Hypertension, Humans, Hypoxia, Pulmonary Artery, Rats, Synchrotrons, X-Ray Microtomography, Pulmonary Arterial Hypertension
- Abstract
Competing Interests: Conflict of interest: C. Westöö declares a regional salary grant for medical resident researchers from ALF Forskningsutrymme för ST-läkare. T. Dreier declares an industrial PhD salary from Excillum AB, and payment to their institution from the Swedish Foundation for Strategic Research (SSF) in connection with the present manuscript. M.E. Kumar declares American Heart Association Scientist Development Grant AHA 16SDG30030006, Stanford Pediatrics startup funds 1246483-200-JHAJH, Stanford Spectrum Child Health Research Institute 1170805-100-GHEBG, Stanford Maternal and Child Health Research Institute Pilot Grant 1220318-108-JHACT, Vera Moulton Wall Center for Pulmonary Vascular Research grant 1144545-401-GHDCK and a Bravo Family Endowed Faculty Scholarship, in connection with the present manuscript. E. Spiekerkoetter declares that they have a research scholarship from Vera Moulton Wall Center for Pulmonary Vascular Disease, in connection with the present manuscript; and that they have received grants from the National Institutes of Health (National Heart, Lung and Blood Institute grants R01HL158868 and R01 HL128734) and Department of Defense (grants PR161256 and PR 181774) in the 36 months prior to manuscript submission; and that they receive royalties from Stanford University for Method of use patent “Use of FK506 for the treatment of Pulmonary Arterial Hypertension”; that they have a provisional US patent for “Enzastaurin and Fragile Histidine Trial (FHIT) Increasing Agents for the Treatment of Pulmonary Hypertension”; and that they are chair of the American Heart Association 3CPR Early Career Committee, and a member of the Stanford University Institutional Review Board. K. Tran-Lundmark declares funding from the Swedish Heart-Lung Foundation, the Crafoord Foundation, the Swedish Society of Medicine, the Knut and Alice Wallenberg Foundation and the Skåne County Council, in connection with the present manuscript; as well as roles as American Thoracic Society (ATS) Pulmonary Circulation Program Committee member (unpaid); American Heart Association (AHA) 3CPR Early Career Committee (unpaid) and Association for European Paediatric and Congenital Cardiology (AEPC) Councillor in the Working Group for Pulmonary Hypertension, Heart Failure and Transplantation (unpaid). All other authors declare no competing interests.
- Published
- 2022
- Full Text
- View/download PDF
16. Cardiac Fibrosis in the Pressure Overloaded Left and Right Ventricle as a Therapeutic Target.
- Author
-
Schimmel K, Ichimura K, Reddy S, Haddad F, and Spiekerkoetter E
- Abstract
Myocardial fibrosis is a remodeling process of the extracellular matrix (ECM) following cardiac stress. "Replacement fibrosis" is a term used to describe wound healing in the acute phase of an injury, such as myocardial infarction. In striking contrast, ECM remodeling following chronic pressure overload insidiously develops over time as "reactive fibrosis" leading to diffuse interstitial and perivascular collagen deposition that continuously perturbs the function of the left (L) or the right ventricle (RV). Examples for pressure-overload conditions resulting in reactive fibrosis in the LV are systemic hypertension or aortic stenosis, whereas pulmonary arterial hypertension (PAH) or congenital heart disease with right sided obstructive lesions such as pulmonary stenosis result in RV reactive fibrosis. In-depth phenotyping of cardiac fibrosis has made it increasingly clear that both forms, replacement and reactive fibrosis co-exist in various etiologies of heart failure. While the role of fibrosis in the pathogenesis of RV heart failure needs further assessment, reactive fibrosis in the LV is a pathological hallmark of adverse cardiac remodeling that is correlated with or potentially might even drive both development and progression of heart failure (HF). Further, LV reactive fibrosis predicts adverse outcome in various myocardial diseases and contributes to arrhythmias. The ability to effectively block pathological ECM remodeling of the LV is therefore an important medical need. At a cellular level, the cardiac fibroblast takes center stage in reactive fibrotic remodeling of the heart. Activation and proliferation of endogenous fibroblast populations are the major source of synthesis, secretion, and deposition of collagens in response to a variety of stimuli. Enzymes residing in the ECM are responsible for collagen maturation and cross-linking. Highly cross-linked type I collagen stiffens the ventricles and predominates over more elastic type III collagen in pressure-overloaded conditions. Research has attempted to identify pro-fibrotic drivers causing fibrotic remodeling. Single key factors such as Transforming Growth Factor β (TGFβ) have been described and subsequently targeted to test their usefulness in inhibiting fibrosis in cultured fibroblasts of the ventricles, and in animal models of cardiac fibrosis. More recently, modulation of phenotypic behaviors like inhibition of proliferating fibroblasts has emerged as a strategy to reduce pathogenic cardiac fibroblast numbers in the heart. Some studies targeting LV reactive fibrosis as outlined above have successfully led to improvements of cardiac structure and function in relevant animal models. For the RV, fibrosis research is needed to better understand the evolution and roles of fibrosis in RV failure. RV fibrosis is seen as an integral part of RV remodeling and presents at varying degrees in patients with PAH and animal models replicating the disease of RV afterload. The extent to which ECM remodeling impacts RV function and thus patient survival is less clear. In this review, we describe differences as well as common characteristics and key players in ECM remodeling of the LV vs. the RV in response to pressure overload. We review pre-clinical studies assessing the effect of anti-fibrotic drug candidates on LV and RV function and their premise for clinical testing. Finally, we discuss the mode of action, safety and efficacy of anti-fibrotic drugs currently tested for the treatment of left HF in clinical trials, which might guide development of new approaches to target right heart failure. We touch upon important considerations and knowledge gaps to be addressed for future clinical testing of anti-fibrotic cardiac therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schimmel, Ichimura, Reddy, Haddad and Spiekerkoetter.)
- Published
- 2022
- Full Text
- View/download PDF
17. Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency.
- Author
-
Sweatt AJ, Miyagawa K, Rhodes CJ, Taylor S, Del Rosario PA, Hsi A, Haddad F, Spiekerkoetter E, Bental-Roof M, Bland RD, Swietlik EM, Gräf S, Wilkins MR, Morrell NW, Nicolls MR, Rabinovitch M, and Zamanian RT
- Subjects
- Adult, Aged, Apoptosis drug effects, Elafin pharmacology, Endothelial Cells drug effects, Female, Humans, Male, Middle Aged, Neovascularization, Physiologic drug effects, Pancreatic Elastase pharmacology, Pulmonary Arterial Hypertension immunology, Pulmonary Arterial Hypertension physiopathology, Pulmonary Artery cytology, Severity of Illness Index, Vascular Resistance, Elafin blood, Leukocyte Elastase blood, Pulmonary Arterial Hypertension blood
- Abstract
Background: Preclinical evidence implicates neutrophil elastase (NE) in pulmonary arterial hypertension (PAH) pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation., Research Question: Are circulating NE and elafin levels abnormal in PAH and are they associated with clinical severity?, Study Design and Methods: In an observational Stanford University PAH cohort (n = 249), plasma NE and elafin levels were measured in comparison with those of healthy control participants (n = 106). NE and elafin measurements were then related to PAH clinical features and relevant ancillary biomarkers. Cox regression models were fitted with cubic spline functions to associate NE and elafin levels with survival. To validate prognostic relationships, we analyzed two United Kingdom cohorts (n = 75 and n = 357). Mixed-effects models evaluated NE and elafin changes during disease progression. Finally, we studied effects of NE-elafin balance on pulmonary artery endothelial cells (PAECs) from patients with PAH., Results: Relative to control participants, patients with PAH were found to have increased NE levels (205.1 ng/mL [interquartile range (IQR), 123.6-387.3 ng/mL] vs 97.6 ng/mL [IQR, 74.4-126.6 ng/mL]; P < .0001) and decreased elafin levels (32.0 ng/mL [IQR, 15.3-59.1 ng/mL] vs 45.5 ng/mL [IQR, 28.1-92.8 ng/mL]; P < .0001) independent of PAH subtype, illness duration, and therapies. Higher NE levels were associated with worse symptom severity, shorter 6-min walk distance, higher N-terminal pro-type brain natriuretic peptide levels, greater right ventricular dysfunction, worse hemodynamics, increased circulating neutrophil levels, elevated cytokine levels, and lower blood BMPR2 expression. In Stanford patients, NE levels of > 168.5 ng/mL portended increased mortality risk after adjustment for known clinical predictors (hazard ratio [HR], 2.52; CI, 1.36-4.65, P = .003) or prognostic cytokines (HR, 2.63; CI, 1.42-4.87; P = .001), and the NE level added incremental value to established PAH risk scores. Similar prognostic thresholds were identified in validation cohorts. Longitudinal NE changes tracked with clinical trends and outcomes. PAH PAECs exhibited increased apoptosis and attenuated angiogenesis when exposed to NE at the level observed in patients' blood. Elafin rescued PAEC homeostasis, yet the required dose exceeded levels found in patients., Interpretation: Blood levels of NE are increased while elafin levels are deficient across PAH subtypes. Higher NE levels are associated with worse clinical disease severity and outcomes, and this target-specific biomarker could facilitate therapeutic development of elafin., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
18. Improving Right Ventricular Function by Increasing BMP Signaling with FK506.
- Author
-
Boehm M, Tian X, Ali MK, Mao Y, Ichimura K, Zhao M, Kuramoto K, Dannewitz Prosseda S, Fajardo G, Dufva MJ, Qin X, Kheyfets VO, Bernstein D, Reddy S, Metzger RJ, Zamanian RT, Haddad F, and Spiekerkoetter E
- Subjects
- Animals, Bone Morphogenetic Protein Receptors, Type II genetics, Bone Morphogenetic Proteins genetics, Fibroblasts metabolism, Fibrosis, Humans, Male, Mice, Mice, Mutant Strains, Myocardium metabolism, Pulmonary Arterial Hypertension drug therapy, Pulmonary Arterial Hypertension genetics, Signal Transduction genetics, Ventricular Function, Right genetics, Bone Morphogenetic Protein Receptors, Type II metabolism, Bone Morphogenetic Proteins metabolism, Pulmonary Arterial Hypertension metabolism, Signal Transduction drug effects, Tacrolimus pharmacology, Ventricular Function, Right drug effects
- Abstract
Right ventricular (RV) function is the predominant determinant of survival in patients with pulmonary arterial hypertension (PAH). In preclinical models, pharmacological activation of BMP (bone morphogenetic protein) signaling with FK506 (tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three patients with end-stage PAH. Whether FK506 has direct effects on the pressure-overloaded right ventricle is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wild-type and heterozygous Bmpr2 mutant mice. RV function and strain were assessed longitudinally via cardiac magnetic resonance imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts and ECs. In mice, low BMP signaling in the right ventricle exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization, and improved RV function and strain over the time course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in human cardiac fibroblasts as a BMPR2 co-receptor to reduce TGFβ1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.
- Published
- 2021
- Full Text
- View/download PDF
19. Arteriovenous Malformations-Current Understanding of the Pathogenesis with Implications for Treatment.
- Author
-
Schimmel K, Ali MK, Tan SY, Teng J, Do HM, Steinberg GK, Stevenson DA, and Spiekerkoetter E
- Subjects
- Animals, Arteries pathology, Arteriovenous Malformations diagnostic imaging, Arteriovenous Malformations pathology, Arteriovenous Malformations therapy, Disease Models, Animal, Humans, Molecular Targeted Therapy, Receptor Cross-Talk, Veins pathology, Arteriovenous Malformations genetics
- Abstract
Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. We discuss past and present accomplishments and challenges in the field and identify research gaps that need to be filled for the successful development of therapeutic strategies in the future.
- Published
- 2021
- Full Text
- View/download PDF
20. Promising therapeutic approaches in pulmonary arterial hypertension.
- Author
-
Ali MK, Ichimura K, and Spiekerkoetter E
- Subjects
- Humans, Signal Transduction, Heart Failure, Hypertension, Pulmonary drug therapy, Pulmonary Arterial Hypertension
- Abstract
Pulmonary arterial hypertension (PAH) is a debilitating multifactorial disease characterized by progressive pulmonary vascular remodeling, elevated pulmonary arterial pressure, and pulmonary vascular resistance, resulting in right ventricular failure and subsequent death. Current available therapies do not reverse the disease, resulting in a persistent high morbidity and mortality. Thus, there is an urgent unmet medical need for novel effective therapies to better treat patients with PAH. Over the past few years, enthusiastic attempts have been made to identify novel effective therapies that address the essential roots of PAH with targeting key signaling pathways in both preclinical models and patients with PAH. This review aims to discuss the most emerging and promising therapeutic interventions in PAH pathogenesis., Competing Interests: Conflict of interest statement E.S. has served as scientific adviser for Selten Pharma, Inc., Vivus (modest). E.S. is listed as inventor on patent applications Use of FK506 for the Treatment of Pulmonary Arterial Hypertension (Serial No 61/481317) and Enzastaurin and Fragile Histidine Trial (FHIT) Increasing Agents for the Treatment of Pulmonary Hypertension (PCT/US2018/033533). M.K.A and K.I. have no conflicts of interest to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
21. Role of Long Non-Coding RNAs in Pulmonary Arterial Hypertension.
- Author
-
Han Y, Ali MK, Dua K, Spiekerkoetter E, and Mao Y
- Subjects
- Animals, Biomarkers metabolism, Gene Editing, Gene Expression Regulation, Humans, Oligonucleotides, Antisense therapeutic use, Pulmonary Arterial Hypertension genetics, Pulmonary Arterial Hypertension physiopathology, Pulmonary Arterial Hypertension therapy, Pulmonary Artery physiopathology, RNA, Long Noncoding genetics, RNAi Therapeutics, Signal Transduction, Ventricular Dysfunction, Right metabolism, Ventricular Dysfunction, Right physiopathology, Ventricular Function, Right, Ventricular Remodeling, Pulmonary Arterial Hypertension metabolism, Pulmonary Artery metabolism, RNA, Long Noncoding metabolism, Vascular Remodeling
- Abstract
Pulmonary arterial hypertension (PAH) is a debilitating condition of the pulmonary circulatory system that occurs in patients of all ages and if untreated, eventually leads to right heart failure and death. Despite existing medical treatment options that improve survival and quality of life, the disease remains incurable. Thus, there is an urgent need to develop novel therapies to treat this disease. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play critical roles in pulmonary vascular remodeling and PAH. LncRNAs are implicated in pulmonary arterial endothelial dysfunction by modulating endothelial cell proliferation, angiogenesis, endothelial mesenchymal transition, and metabolism. LncRNAs are also involved in inducing different pulmonary arterial vascular smooth muscle cell phenotypes, such as cell proliferation, apoptosis, migration, regulation of the phenotypic switching, and cell cycle. LncRNAs are essential regulators of gene expression that affect various diseases at the chromatin, transcriptional, post-translational, and even post-translational levels. Here, we focus on the role of LncRNAs and their molecular mechanisms in the pathogenesis of PAH. We also discuss the current research challenge and potential biomarker and therapeutic potentials of lncRNAs in PAH.
- Published
- 2021
- Full Text
- View/download PDF
22. Pulmonary arterial banding in mice may be a suitable model for studies on ventricular mechanics in pediatric pulmonary arterial hypertension.
- Author
-
Dufva MJ, Boehm M, Ichimura K, Truong U, Qin X, Tabakh J, Hunter KS, Ivy D, Spiekerkoetter E, and Kheyfets VO
- Subjects
- Animals, Child, Heart Ventricles diagnostic imaging, Humans, Mice, Predictive Value of Tests, Pulmonary Artery diagnostic imaging, Pulmonary Artery surgery, Retrospective Studies, Ventricular Function, Right, Pulmonary Arterial Hypertension, Ventricular Dysfunction, Right diagnostic imaging, Ventricular Dysfunction, Right etiology
- Abstract
Background: The role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV-pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children., Methods: Balanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48 h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance (RV_E
es , a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_Ees was assessed via the single beat method., Results: LV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p = 0.004) and pediatric PAH patients (p < 0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_Ees in PAB (r = 0.91, p = 0.05) and PAH subjects (r = 0.51, p = 0.04). In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p < 0.05) reduced under hypertensive conditions in both PAB mice and children with PAH., Conclusions: The PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency.- Published
- 2021
- Full Text
- View/download PDF
23. Targeted proteomics of right heart adaptation to pulmonary arterial hypertension.
- Author
-
Amsallem M, Sweatt AJ, Arthur Ataam J, Guihaire J, Lecerf F, Lambert M, Ghigna MR, Ali MK, Mao Y, Fadel E, Rabinovitch M, de Jesus Perez V, Spiekerkoetter E, Mercier O, Haddad F, and Zamanian RT
- Subjects
- Animals, Cohort Studies, Familial Primary Pulmonary Hypertension, Humans, Mice, Natriuretic Peptide, Brain, Proteomics, Hypertension, Pulmonary, Pulmonary Arterial Hypertension
- Abstract
No prior proteomic screening study has centred on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 (discovery cohort) and 76 (validation cohort) PAH patients. The association between proteomic markers and RHMP, defined by the Mayo right heart score (combining RV strain, New York Heart Association (NYHA) class and N-terminal pro-brain natriuretic peptide (NT-proBNP)) and Stanford score (RV end-systolic remodelling index, NYHA class and NT-proBNP), was assessed by partial least squares regression. Biomarker expression was measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatocyte growth factor (HGF), stem cell growth factor-β, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk of heart failure who warrant closer follow-up and intensified therapy., Competing Interests: Conflict of interest: M. Amsallem has received a 2016 Young Investigator Seed Grant from the Vera Moulton Wall Center at Stanford, a 2019–2020 Stanford Maternal and Child Health Research Institute research seed grant, a research grant from Actelion-Janssen and speaker fees from Bayer. Conflict of interest: A.J. Sweatt has nothing to disclose. Conflict of interest: J. Arthur Ataam has nothing to disclose. Conflict of interest: J. Guihaire has nothing to disclose. Conflict of interest: F. Lecerf has nothing to disclose. Conflict of interest: M. Lambert has nothing to disclose. Conflict of interest: M.R. Ghigna has nothing to disclose. Conflict of interest: M.K. Ali has nothing to disclose. Conflict of interest: Y. Mao has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: M. Rabinovitch has nothing to disclose. Conflict of interest: V. de Jesus Perez has nothing to disclose. Conflict of interest: E. Spiekerkoetter is funded by Stanford Cardiovascular Institute, National Heart Lung Blood Institute (NHLBI) at the National Institute of Health (NIH) grant R01 HL128734 and Department of Defense grant PR161256. Conflict of interest: O. Mercier has been supported by a public grant overseen by the French National Research Agency as part of the second Investissement d'Avenir program (ANR-15-RHUS-0002). Conflict of interest: F. Haddad has received research grants from Actelion-Janssen and Philips. Conflict of interest: R.T. Zamanian has nothing to disclose., (Copyright ©ERS 2021.)
- Published
- 2021
- Full Text
- View/download PDF
24. Comparative analysis on the anti-inflammatory/immune effect of mesenchymal stem cell therapy for the treatment of pulmonary arterial hypertension.
- Author
-
Oh S, Jang AY, Chae S, Choi S, Moon J, Kim M, Spiekerkoetter E, Zamanian RT, Yang PC, Hwang D, Byun K, and Chung WJ
- Subjects
- Animals, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Cell Proliferation genetics, Cord Blood Stem Cell Transplantation, Disease Models, Animal, Gene Expression Regulation genetics, Humans, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells metabolism, Pulmonary Arterial Hypertension genetics, Pulmonary Arterial Hypertension pathology, Pulmonary Artery growth & development, Pulmonary Artery pathology, Rats, Ventricular Function, Right genetics, Cell- and Tissue-Based Therapy, Mesenchymal Stem Cell Transplantation, Pulmonary Arterial Hypertension therapy, Vascular Remodeling genetics
- Abstract
Despite the advancement of targeted therapy for pulmonary arterial hypertension (PAH), poor prognosis remains a reality. Mesenchymal stem cells (MSCs) are one of the most clinically feasible alternative treatment options. We compared the treatment effects of adipose tissue (AD)-, bone marrow (BD)-, and umbilical cord blood (UCB)-derived MSCs in the rat monocrotaline-induced pulmonary hypertension (PH) model. The greatest improvement in the right ventricular function was observed in the UCB-MSCs treated group. The UCB-MSCs treated group also exhibited the greatest improvement in terms of the largest decrease in the medial wall thickness, perivascular fibrosis, and vascular cell proliferation, as well as the lowest levels of recruitment of innate and adaptive immune cells and associated inflammatory cytokines. Gene expression profiling of lung tissue confirmed that the UCB-MSCs treated group had the most notably attenuated immune and inflammatory profiles. Network analysis further revealed that the UCB-MSCs group had the greatest therapeutic effect in terms of the normalization of all three classical PAH pathways. The intravenous injection of the UCB-MSCs, compared with those of other MSCs, showed superior therapeutic effects in the PH model for the (1) right ventricular function, (2) vascular remodeling, (3) immune/inflammatory profiles, and (4) classical PAH pathways.
- Published
- 2021
- Full Text
- View/download PDF
25. Novel Advances in Modifying BMPR2 Signaling in PAH.
- Author
-
Dannewitz Prosseda S, Ali MK, and Spiekerkoetter E
- Subjects
- Animals, Bone Morphogenetic Protein Receptors, Type II agonists, Bone Morphogenetic Protein Receptors, Type II metabolism, Disease Models, Animal, Genetic Therapy trends, Humans, Loss of Function Mutation, Pulmonary Arterial Hypertension genetics, Signal Transduction genetics, Bone Morphogenetic Protein Receptors, Type II genetics, Genetic Therapy methods, Pulmonary Arterial Hypertension therapy
- Abstract
Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary arteries, that is characterized by progressive narrowing of the pulmonary arterial lumen and increased pulmonary vascular resistance, ultimately leading to right ventricular dysfunction, heart failure and premature death. Current treatments mainly target pulmonary vasodilation and leave the progressive vascular remodeling unchecked resulting in persistent high morbidity and mortality in PAH even with treatment. Therefore, novel therapeutic strategies are urgently needed. Loss of function mutations of the Bone Morphogenetic Protein Receptor 2 (BMPR2) are the most common genetic factor in hereditary forms of PAH, suggesting that the BMPR2 pathway is fundamentally important in the pathogenesis. Dysfunctional BMPR2 signaling recapitulates the cellular abnormalities in PAH as well as the pathobiology in experimental pulmonary hypertension (PH). Approaches to restore BMPR2 signaling by increasing the expression of BMPR2 or its downstream signaling targets are currently actively explored as novel ways to prevent and improve experimental PH as well as PAH in patients. Here, we summarize existing as well as novel potential treatment strategies for PAH that activate the BMPR2 receptor pharmaceutically or genetically, increase the receptor availability at the cell surface, or reconstitute downstream BMPR2 signaling.
- Published
- 2020
- Full Text
- View/download PDF
26. Repurposing of medications for pulmonary arterial hypertension.
- Author
-
Toshner M, Spiekerkoetter E, Bogaard H, Hansmann G, Nikkho S, and Prins KW
- Abstract
This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem., (© The Author(s) 2020.)
- Published
- 2020
- Full Text
- View/download PDF
27. A Notch3-Marked Subpopulation of Vascular Smooth Muscle Cells Is the Cell of Origin for Occlusive Pulmonary Vascular Lesions.
- Author
-
Steffes LC, Froistad AA, Andruska A, Boehm M, McGlynn M, Zhang F, Zhang W, Hou D, Tian X, Miquerol L, Nadeau K, Metzger RJ, Spiekerkoetter E, and Kumar ME
- Subjects
- Animals, Disease Models, Animal, Female, Humans, Mice, Muscle, Smooth, Vascular metabolism, Hypertension, Pulmonary physiopathology, Myocytes, Smooth Muscle metabolism, Receptor, Notch3 metabolism, Vascular Remodeling immunology
- Abstract
Background: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by profound vascular remodeling in which pulmonary arteries narrow because of medial thickening and occlusion by neointimal lesions, resulting in elevated pulmonary vascular resistance and right heart failure. Therapies targeting the neointima would represent a significant advance in PAH treatment; however, our understanding of the cellular events driving neointima formation, and the molecular pathways that control them, remains limited., Methods: We comprehensively map the stepwise remodeling of pulmonary arteries in a robust, chronic inflammatory mouse model of pulmonary hypertension. This model demonstrates pathological features of the human disease, including increased right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation, and perivascular inflammation. Using genetic lineage tracing, clonal analysis, multiplexed in situ hybridization, immunostaining, deep confocal imaging, and staged pharmacological inhibition, we define the cell behaviors underlying each stage of vascular remodeling and identify a pathway required for neointima formation., Results: Neointima arises from smooth muscle cells (SMCs) and not endothelium. Medial SMCs proliferate broadly to thicken the media, after which a small number of SMCs are selected to establish the neointima. These neointimal founder cells subsequently undergoing massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery SMC population is heterogeneous, and we identify a Notch3-marked minority subset of SMCs as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension., Conclusions: This work describes the first nongenetically driven murine model of pulmonary hypertension (PH) that generates robust and diffuse occlusive neointimal lesions across the pulmonary vascular bed and does so in a stereotyped timeframe. We uncover distinct cellular and molecular mechanisms underlying medial thickening and neointima formation and highlight novel transcriptional, behavioral, and pathogenic heterogeneity within pulmonary artery SMCs. In this model, inflammation is sufficient to generate characteristic vascular pathologies and physiological measures of human PAH. We hope that identifying the molecular cues regulating each stage of vascular remodeling will open new avenues for therapeutic advancements in the treatment of PAH.
- Published
- 2020
- Full Text
- View/download PDF
28. Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of pulmonary artery de-banding.
- Author
-
Boehm M, Tian X, Mao Y, Ichimura K, Dufva MJ, Ali K, Dannewitz Prosseda S, Shi Y, Kuramoto K, Reddy S, Kheyfets VO, Metzger RJ, and Spiekerkoetter E
- Subjects
- Animals, Arterial Pressure, Disease Models, Animal, Exercise Tolerance, Fibroblasts metabolism, Fibroblasts pathology, Fibrosis, Hypertrophy, Right Ventricular etiology, Hypertrophy, Right Ventricular metabolism, Hypertrophy, Right Ventricular pathology, Male, Mice, Inbred C57BL, Myocardium metabolism, Myocardium pathology, Pulmonary Arterial Hypertension etiology, Pulmonary Arterial Hypertension physiopathology, Pulmonary Artery physiopathology, Recovery of Function, Suture Techniques, Time Factors, Ventricular Dysfunction, Right etiology, Ventricular Dysfunction, Right metabolism, Ventricular Dysfunction, Right pathology, Hypertrophy, Right Ventricular physiopathology, Pulmonary Artery surgery, Ventricular Dysfunction, Right physiopathology, Ventricular Function, Right, Ventricular Remodeling
- Abstract
Aims: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events., Methods and Results: Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB)-after RV dysfunction and structural remodelling were established-initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery., Conclusion: We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodelling events., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
- Full Text
- View/download PDF
29. Targeting BMPR2 Trafficking with Chaperones: An Important Step toward Precision Medicine in Pulmonary Arterial Hypertension.
- Author
-
Andruska A, Ali MK, and Spiekerkoetter E
- Subjects
- Cysteine, Familial Primary Pulmonary Hypertension, Humans, Precision Medicine, Bone Morphogenetic Protein Receptors, Type II, Pulmonary Arterial Hypertension
- Published
- 2020
- Full Text
- View/download PDF
30. The hallmarks of severe pulmonary arterial hypertension: the cancer hypothesis-ten years later.
- Author
-
Cool CD, Kuebler WM, Bogaard HJ, Spiekerkoetter E, Nicolls MR, and Voelkel NF
- Subjects
- Animals, Apoptosis, Autoimmunity, Humans, Neoplasm Proteins metabolism, Lung Neoplasms pathology, Models, Biological, Pulmonary Arterial Hypertension pathology
- Abstract
Severe forms of pulmonary arterial hypertension (PAH) are most frequently the consequence of a lumen-obliterating angiopathy. One pathobiological model is that the initial pulmonary vascular endothelial cell injury and apoptosis is followed by the evolution of phenotypically altered, apoptosis-resistant, proliferating cells and an inflammatory vascular immune response. Although there may be a vasoconstrictive disease component, the increased pulmonary vascular shear stress in established PAH is caused largely by the vascular wall pathology. In this review, we revisit the "quasi-malignancy concept" of severe PAH and examine to what extent the hallmarks of PAH can be compared with the hallmarks of cancer. The cancer model of severe PAH, based on the growth of abnormal vascular and bone marrow-derived cells, may enable the emergence of novel cell-based PAH treatment strategies.
- Published
- 2020
- Full Text
- View/download PDF
31. The left ventricle undergoes biomechanical and gene expression changes in response to increased right ventricular pressure overload.
- Author
-
Kheyfets VO, Dufva MJ, Boehm M, Tian X, Qin X, Tabakh JE, Truong U, Ivy D, and Spiekerkoetter E
- Subjects
- Animals, Disease Models, Animal, Fibrosis genetics, Fibrosis metabolism, Heart Ventricles metabolism, Heart Ventricles pathology, Heart Ventricles physiopathology, Hypertension genetics, Hypertension metabolism, Male, Mice, Mice, Inbred C57BL, Pulmonary Artery metabolism, Pulmonary Artery pathology, Pulmonary Artery physiopathology, Ventricular Dysfunction, Right genetics, Ventricular Dysfunction, Right metabolism, Ventricular Function, Left, Ventricular Pressure, Fibrosis pathology, Gene Expression Regulation, Hypertension pathology, Ventricular Dysfunction, Right physiopathology
- Abstract
Pulmonary hypertension (PH) results in right ventricular (RV) pressure overload and eventual failure. Current research efforts have focused on the RV while overlooking the left ventricle (LV), which is responsible for mechanically assisting the RV during contraction. The objective of this study is to evaluate the biomechanical and gene expression changes occurring in the LV due to RV pressure overload in a mouse model. Nine male mice were divided into two groups: (a) pulmonary arterial banding (PAB, N = 4) and (b) sham surgery (Sham, N = 5). Tagged and steady-state free precision cardiac MRI was performed on each mouse at 1, 4, and 7 weeks after surgery. At/week7, the mice were euthanized following right/left heart catheterization with RV/LV tissue harvested for histology and gene expression (using RT-PCR) studies. Compared to Sham mice, the PAB group revealed a significantly decreased LV and RV ejection fraction, and LV maximum torsion and torsion rate, within the first week after banding. In the PAB group, there was also a slight but significant increase in LV perivascular fibrosis, which suggests elevated myocardial stress. LV fibrosis was also accompanied with changes in gene expression in the hypertensive group, which was correlated with LV contractile mechanics. In fact, principal component (PC) analysis of LV gene expression effectively separated Sham and PAB mice along PC2. Changes in LV contractile mechanics were also significantly correlated with unfavorable changes in RV contractile mechanics, but a direct causal relationship was not established. In conclusion, a purely biomechanical insult of RV pressure overload resulted in biomechanical and transcriptional changes in both the RV and LV. Given that the RV relies on the LV for contractile energy assistance, considering the LV could provide prognostic and therapeutic targets for treating RV failure in PH., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)
- Published
- 2020
- Full Text
- View/download PDF
32. Hot topics in the mechanisms of pulmonary arterial hypertension disease: cancer-like pathobiology, the role of the adventitia, systemic involvement, and right ventricular failure.
- Author
-
Spiekerkoetter E, Goncharova EA, Guignabert C, Stenmark K, Kwapiszewska G, Rabinovitch M, Voelkel N, Bogaard HJ, Graham B, Pullamsetti SS, and Kuebler WM
- Abstract
In order to intervene appropriately and develop disease-modifying therapeutics for pulmonary arterial hypertension, it is crucial to understand the mechanisms of disease pathogenesis and progression. We herein discuss four topics of disease mechanisms that are currently highly debated, yet still unsolved, in the field of pulmonary arterial hypertension. Is pulmonary arterial hypertension a cancer-like disease? Does the adventitia play an important role in the initiation of pulmonary vascular remodeling? Is pulmonary arterial hypertension a systemic disease? Does capillary loss drive right ventricular failure? While pulmonary arterial hypertension does not replicate all features of cancer, anti-proliferative cancer therapeutics might still be beneficial in pulmonary arterial hypertension if monitored for safety and tolerability. It was recognized that the adventitia as a cell-rich compartment is important in the disease pathogenesis of pulmonary arterial hypertension and should be a therapeutic target, albeit the data are inconclusive as to whether the adventitia is involved in the initiation of neointima formation. There was agreement that systemic diseases can lead to pulmonary arterial hypertension and that pulmonary arterial hypertension can have systemic effects related to the advanced lung pathology, yet there was less agreement on whether idiopathic pulmonary arterial hypertension is a systemic disease per se. Despite acknowledging the limitations of exactly assessing vascular density in the right ventricle, it was recognized that the failing right ventricle may show inadequate vascular adaptation resulting in inadequate delivery of oxygen and other metabolites. Although the debate was not meant to result in a definite resolution of the specific arguments, it sparked ideas about how we might resolve the discrepancies by improving our disease modeling (rodent models, large-animal studies, studies of human cells, tissues, and organs) as well as standardization of the models. Novel experimental approaches, such as lineage tracing and better three-dimensional imaging of experimental as well as human lung and heart tissues, might unravel how different cells contribute to the disease pathology., (© The Author(s) 2019.)
- Published
- 2019
- Full Text
- View/download PDF
33. Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension.
- Author
-
Sommer N, Droege F, Gamen KE, Geisthoff U, Gall H, Tello K, Richter MJ, Deubner LM, Schmiedel R, Hecker M, Spiekerkoetter E, Wirsching K, Seeger W, Ghofrani HA, and Pullamsetti S
- Abstract
Pulmonary arterial hypertension (PAH) can be found in patients suffering from a loss-of-function mutation of the gene encoding for the activin receptor-like kinase 1 (ALK-1), a bone morphogenetic protein (BMP) type 1 receptor. Interestingly, ALK-1 mutations also lead to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease characterized by arteriovenous malformations (AVMs) leading to potentially life-threatening bleeding complications such as epistaxis. Current therapeutic options for both diseases are limited and often only temporary or accompanied by severe side effects. Here, we report of a patient with a mutation of the ALK-1 gene suffering from both HHT and PAH. Recently, it was shown that tacrolimus increased ALK-1 signaling and had beneficial effects in selected end-stage PAH patients. We thus hypothesized that treatment with tacrolimus may prevent disease progression in this patient. Surprisingly, treatment with low-dose tacrolimus dramatically improved his HHT-associated epistaxis but did not attenuate progression of PAH.
- Published
- 2019
- Full Text
- View/download PDF
34. New and Emerging Therapies for Pulmonary Arterial Hypertension.
- Author
-
Spiekerkoetter E, Kawut SM, and de Jesus Perez VA
- Subjects
- Combined Modality Therapy, Disease Progression, Female, Forecasting, Humans, Hypertension, Pulmonary diagnosis, Hypertension, Pulmonary epidemiology, Male, Prognosis, Risk Assessment, Severity of Illness Index, Survival Analysis, Antihypertensive Agents therapeutic use, Drug Delivery Systems, Heart Failure prevention & control, Hypertension, Pulmonary therapy, Precision Medicine trends
- Abstract
Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that causes right ventricular dysfunction and exercise limitation and progresses to death. New findings from translational studies have suggested alternative pathways for treatment. These avenues include sex hormones, genetic abnormalities and DNA damage, elastase inhibition, metabolic dysfunction, cellular therapies, and anti-inflammatory approaches. Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH. Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.
- Published
- 2019
- Full Text
- View/download PDF
35. FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension.
- Author
-
Dannewitz Prosseda S, Tian X, Kuramoto K, Boehm M, Sudheendra D, Miyagawa K, Zhang F, Solow-Cordero D, Saldivar JC, Austin ED, Loyd JE, Wheeler L, Andruska A, Donato M, Wang L, Huebner K, Metzger RJ, Khatri P, and Spiekerkoetter E
- Subjects
- Animals, Bone Morphogenetic Protein Receptors, Type II genetics, Disease Models, Animal, Familial Primary Pulmonary Hypertension metabolism, Female, Humans, Indoles pharmacology, Lung metabolism, Male, Mice, Mice, Inbred C57BL, Rats, Rats, Sprague-Dawley, Signal Transduction drug effects, Acid Anhydride Hydrolases genetics, Familial Primary Pulmonary Hypertension genetics, Genes, Modifier genetics, Neoplasm Proteins genetics
- Abstract
Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing of pulmonary arteries, resulting in right heart failure and death. BMPR2 (bone morphogenetic protein receptor type 2) mutations account for most familial PAH forms whereas reduced BMPR2 is present in many idiopathic PAH forms, suggesting dysfunctional BMPR2 signaling to be a key feature of PAH. Modulating BMPR2 signaling is therapeutically promising, yet how BMPR2 is downregulated in PAH is unclear., Objectives: We intended to identify and pharmaceutically target BMPR2 modifier genes to improve PAH., Methods: We combined siRNA high-throughput screening of >20,000 genes with a multicohort analysis of publicly available PAH RNA expression data to identify clinically relevant BMPR2 modifiers. After confirming gene dysregulation in tissue from patients with PAH, we determined the functional roles of BMPR2 modifiers in vitro and tested the repurposed drug enzastaurin for its propensity to improve experimental pulmonary hypertension (PH)., Measurements and Main Results: We discovered FHIT (fragile histidine triad) as a novel BMPR2 modifier. BMPR2 and FHIT expression were reduced in patients with PAH. FHIT reductions were associated with endothelial and smooth muscle cell dysfunction, rescued by enzastaurin through a dual mechanism: upregulation of FHIT as well as miR17-5 repression. Fhit
-/- mice had exaggerated hypoxic PH and failed to recover in normoxia. Enzastaurin reversed PH in the Sugen5416/hypoxia/normoxia rat model, by improving right ventricular systolic pressure, right ventricular hypertrophy, cardiac fibrosis, and vascular remodeling., Conclusions: This study highlights the importance of the novel BMPR2 modifier FHIT in PH and the clinical value of the repurposed drug enzastaurin as a potential novel therapeutic strategy to improve PAH.- Published
- 2019
- Full Text
- View/download PDF
36. Drug repositioning in pulmonary arterial hypertension: challenges and opportunities.
- Author
-
Grinnan D, Trankle C, Andruska A, Bloom B, and Spiekerkoetter E
- Abstract
Despite many advances in medical therapy for pulmonary arterial hypertension (PAH) over the past 20 years, long-term survival is still poor. Novel therapies which target the underlying pathology of PAH and which could be added to current vasodilatory therapies to halt disease progression and potentially reverse pulmonary vascular remodeling are highly sought after. Given the high attrition rates, substantial costs, and slow pace of new drug development, repositioning of "old" drugs is increasingly becoming an attractive path to identify novel treatment options, especially for a rare disease such as PAH. We here summarize the limitations of current PAH therapy, the general concept of repurposing and repositioning, success stories of approved repositioned drugs in PAH as well as novel repositioned drugs that show promise in preclinical models of pulmonary hypertension (PH) and are currently tested in clinical trials. We furthermore discuss various data-driven as well as experimental approaches currently used to identify repurposed drug candidates and review challenges for the "repositioning community" with regards to funding and patent and regulatory considerations, and to illustrate opportunities for collaborative solutions for drug repositioning relevant to PAH.
- Published
- 2019
- Full Text
- View/download PDF
37. A pro-con debate: current controversies in PAH pathogenesis at the American Thoracic Society International Conference in 2017.
- Author
-
Kuebler WM, Nicolls MR, Olschewski A, Abe K, Rabinovitch M, Stewart D, Chan SY, Morrell NW, Archer SL, and Spiekerkoetter E
- Subjects
- Animals, Humans, Hypertension, Pulmonary etiology, Hypertension, Pulmonary pathology, Pulmonary Artery physiopathology
- Abstract
The following review summarizes the pro-con debate about current controversies regarding the pathogenesis of pulmonary arterial hypertension (PAH) that took place at the American Thoracic Society Conference in May 2017. Leaders in the field of PAH research discussed the importance of the immune system, the role of hemodynamic stress and endothelial apoptosis, as well as bone morphogenetic protein receptor-2 signaling in PAH pathogenesis. Whereas this summary does not intend to resolve obvious conflicts in opinion, we hope that the presented arguments entice further discussions and draw a new generation of enthusiastic researchers into this vibrant field of science to bridge existing gaps for a better understanding and therapy of this fatal disease.
- Published
- 2018
- Full Text
- View/download PDF
38. Exome data clouds the pathogenicity of genetic variants in Pulmonary Arterial Hypertension.
- Author
-
Abbasi Y, Jabbari J, Jabbari R, Glinge C, Izadyar SB, Spiekerkoetter E, Zamanian RT, Carlsen J, and Tfelt-Hansen J
- Subjects
- Exome, Humans, Bone Morphogenetic Protein Receptors, Type II genetics, Carrier Proteins genetics, Codon, Nonsense, DNA-Binding Proteins genetics, Endoglin genetics, Hypertension, Pulmonary genetics, Mutation, Missense, Nuclear Proteins genetics
- Abstract
Background: We aimed to provide a set of previously reported PAH-associated missense and nonsense variants, and evaluate the pathogenicity of those variants., Methods: The Human Gene Mutation Database, PubMed, and Google Scholar were searched for previously reported PAH-associated genes and variants. Thereafter, both exome sequencing project and exome aggregation consortium as background population searched for previously reported PAH-associated missense and nonsense variants. The pathogenicity of previously reported PAH-associated missense variants evaluated by using four in silico prediction tools., Results: In total, 14 PAH-associated genes and 180 missense and nonsense variants were gathered. The BMPR2, the most frequent reported gene, encompasses 135 of 180 missense and nonsense variants. The exome sequencing project comprised 9, and the exome aggregation consortium counted 25 of 180 PAH-associated missense and nonsense variants. The TOPBP1 and ENG genes are unlikely to be the monogenic cause of PAH pathogenesis based on allele frequency in background population and prediction analysis., Conclusion: This is the first evaluation of previously reported PAH-associated missense and nonsense variants. The BMPR2 identified as the major gene out of 14 PAH-associated genes. Based on findings, the ENG and TOPBP1 gene are not likely to be the monogenic cause of PAH., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2018
- Full Text
- View/download PDF
39. Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension.
- Author
-
Andruska A and Spiekerkoetter E
- Subjects
- Animals, Bone Morphogenetic Protein Receptors, Type II genetics, Bone Morphogenetic Protein Receptors, Type II metabolism, Cardiovascular Physiological Phenomena, Cardiovascular System metabolism, Familial Primary Pulmonary Hypertension metabolism, Familial Primary Pulmonary Hypertension physiopathology, Gene Expression Regulation, Humans, Immune System immunology, Immune System metabolism, Mutation, Myocardium metabolism, Organ Specificity genetics, Organ Specificity immunology, Pulmonary Artery metabolism, Pulmonary Artery pathology, Pulmonary Circulation genetics, Signal Transduction, Bone Morphogenetic Protein Receptors, Type II deficiency, Familial Primary Pulmonary Hypertension etiology, Genetic Association Studies, Genetic Predisposition to Disease
- Abstract
Since its association with familial pulmonary arterial hypertension (PAH) in 2000, Bone Morphogenetic Protein Receptor II (BMPR2) and its related signaling pathway have become recognized as a key regulator of pulmonary vascular homeostasis. Herein, we define BMPR2 deficiency as either an inactivation of the receptor, decreased receptor expression, or an impairment of the receptor's downstream signaling pathway. Although traditionally the phenotypic consequences of BMPR2 deficiency in PAH have been thought to be limited to the pulmonary vasculature, there is evidence that abnormalities in BMPR2 signaling may have consequences in many other organ systems and cellular compartments. Revisiting how BMPR2 functions throughout health and disease in cells and organs beyond the lung vasculature may provide insight into the contribution of these organ systems to PAH pathogenesis as well as the potential systemic manifestation of PAH. Here we review our knowledge of the consequences of BMPR2 deficiency across multiple organ systems.
- Published
- 2018
- Full Text
- View/download PDF
40. Update in Pulmonary Vascular Disease 2016 and 2017.
- Author
-
Brittain EL, Thennapan T, Maron BA, Chan SY, Austin ED, Spiekerkoetter E, Bogaard HJ, Guignabert C, Paulin R, Machado RF, and Yu PB
- Subjects
- Humans, Hypertension, Pulmonary diagnosis, Hypertension, Pulmonary genetics, Vascular Diseases diagnosis, Vascular Diseases genetics, Hypertension, Pulmonary drug therapy, Hypertension, Pulmonary physiopathology, Lung physiopathology, Vascular Diseases drug therapy, Vascular Diseases physiopathology
- Published
- 2018
- Full Text
- View/download PDF
41. Career Development of Young Physician-Scientists in the Cardiovascular Sciences: Perspective and Advice From the Early Career Committee of the Cardiopulmonary, Critical Care, and Resuscitation Council of the American Heart Association.
- Author
-
Agarwal S, Spiekerkoetter E, Austin ED, de Jesus Perez V, Dezfulian C, Maron BA, Ryan JJ, Starks MA, Yu PB, Bonnet S, and Perman SM
- Subjects
- Burnout, Professional prevention & control, Burnout, Professional psychology, Humans, Mentors, Physicians, Women psychology, Research Support as Topic, Self Care, Time Management, Work Engagement, Cardiology, Career Mobility, Laboratory Personnel psychology, Physicians psychology
- Published
- 2018
- Full Text
- View/download PDF
42. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension.
- Author
-
Spiekerkoetter E, Sung YK, Sudheendra D, Scott V, Del Rosario P, Bill M, Haddad F, Long-Boyle J, Hedlin H, and Zamanian RT
- Subjects
- Adult, Antihypertensive Agents adverse effects, Double-Blind Method, Epoprostenol administration & dosage, Epoprostenol adverse effects, Exercise Tolerance, Female, Humans, Linear Models, Male, Middle Aged, Nausea chemically induced, Tacrolimus adverse effects, Treatment Outcome, Walk Test, Young Adult, Antihypertensive Agents administration & dosage, Bone Morphogenetic Protein Receptors, Type II metabolism, Hypertension, Pulmonary drug therapy, Tacrolimus administration & dosage
- Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease characterised by occlusive pulmonary vasculopathy. Activation of bone morphogenetic protein receptor 2 (BMPR2) signalling by FK506 (tacrolimus) reverses occlusive vasculopathy in rodent PAH models. Here, we determined the safety and tolerability of low-level FK506 therapy in stable PAH patients.We performed a randomised, double-blind, placebo-controlled, 16-week, single-centre, phase IIa trial in PAH patients with New York Heart Association functional class II/III symptoms using three FK506 target levels (<2, 2-3 and 3-5 ng·mL
-1 ). 23 patients were randomised and 20 patients completed the trial.FK506 was generally well tolerated, with nausea/diarrhoea being the most commonly reported adverse event and no observation of line infections in patients on intravenous prostacyclin therapy. PAH patients had significantly lower BMPR2 expression in peripheral blood mononuclear cells versus healthy controls (n=13; p=0.005), which improved after FK506 treatment. While we observed that some patients responded with a pronounced increase in BMPR2 expression as well as improvement in 6-min walk distance, and serological and echocardiographic parameters of heart failure, these changes were not significant.Low-level FK506 is well tolerated and increases BMPR2 in subsets of PAH patients. These results support the study of FK506 in a phase IIb efficacy trial., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)- Published
- 2017
- Full Text
- View/download PDF
43. RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension.
- Author
-
Rhodes CJ, Im H, Cao A, Hennigs JK, Wang L, Sa S, Chen PI, Nickel NP, Miyagawa K, Hopper RK, Tojais NF, Li CG, Gu M, Spiekerkoetter E, Xian Z, Chen R, Zhao M, Kaschwich M, Del Rosario PA, Bernstein D, Zamanian RT, Wu JC, Snyder MP, and Rabinovitch M
- Subjects
- Adolescent, Adult, Animals, Cells, Cultured, Familial Primary Pulmonary Hypertension physiopathology, Female, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Signal Transduction genetics, Transcriptome genetics, Young Adult, Bone Morphogenetic Protein Receptors, Type II genetics, Endothelium, Vascular physiopathology, Familial Primary Pulmonary Hypertension genetics, Sequence Analysis, RNA methods
- Abstract
Rationale: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function., Objectives: RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts., Methods: The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse., Measurements and Main Results: Fold differences in 10 genes were significant (P < 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries., Conclusions: The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.
- Published
- 2015
- Full Text
- View/download PDF
44. Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension.
- Author
-
Spiekerkoetter E, Sung YK, Sudheendra D, Bill M, Aldred MA, van de Veerdonk MC, Vonk Noordegraaf A, Long-Boyle J, Dash R, Yang PC, Lawrie A, Swift AJ, Rabinovitch M, and Zamanian RT
- Subjects
- Adult, Double-Blind Method, Female, Humans, Middle Aged, Treatment Outcome, Hypertension, Pulmonary drug therapy, Immunosuppressive Agents therapeutic use, Tacrolimus therapeutic use
- Published
- 2015
- Full Text
- View/download PDF
45. Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling.
- Author
-
Nickel NP, Spiekerkoetter E, Gu M, Li CG, Li H, Kaschwich M, Diebold I, Hennigs JK, Kim KY, Miyagawa K, Wang L, Cao A, Sa S, Jiang X, Stockstill RW, Nicolls MR, Zamanian RT, Bland RD, and Rabinovitch M
- Subjects
- Animals, Apoptosis drug effects, Cells, Cultured, Endothelial Cells drug effects, Humans, Myocytes, Smooth Muscle drug effects, Pancreatic Elastase drug effects, Rats, Bone Morphogenetic Protein Receptors, Type II drug effects, Caveolin 1 drug effects, Elafin pharmacology, Hypertension, Pulmonary drug therapy, Protease Inhibitors pharmacology, Signal Transduction drug effects
- Abstract
Rationale: Pulmonary arterial hypertension is characterized by endothelial dysfunction, impaired bone morphogenetic protein receptor 2 (BMPR2) signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates hypoxic pulmonary hypertension in mice, but its potential to improve endothelial function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown., Objectives: To assess elafin-mediated regression of pulmonary vascular pathology in rats and in lung explants from patients with pulmonary hypertension. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells and to elucidate the underlying mechanism., Methods: Rats with pulmonary hypertension induced by vascular endothelial growth factor receptor blockade and hypoxia (Sugen/hypoxia) as well as lung organ cultures from patients with pulmonary hypertension were used to assess elafin-mediated reversibility of pulmonary vascular disease. Pulmonary arterial endothelial cells from patients and control subjects were used to determine the efficacy and mechanism of elafin-mediated BMPR2 signaling., Measurements and Main Results: In Sugen/hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a BMPR2 target. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and decreased neointimal lesions in lung organ culture. In normal and patient pulmonary artery endothelial cells, elafin promoted angiogenesis by increasing pSMAD-dependent and -independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of endothelial surface caveolin-1., Conclusions: Elafin reverses obliterative changes in pulmonary arteries via elastase inhibition and caveolin-1-dependent amplification of BMPR2 signaling.
- Published
- 2015
- Full Text
- View/download PDF
46. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors.
- Author
-
Shin K, Lim A, Zhao C, Sahoo D, Pan Y, Spiekerkoetter E, Liao JC, and Beachy PA
- Subjects
- Animals, Disease Progression, Humans, Mice, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms metabolism, Cell Differentiation, Hedgehog Proteins metabolism, Signal Transduction, Stromal Cells metabolism, Urinary Bladder pathology, Urinary Bladder Neoplasms pathology
- Abstract
Hedgehog (Hh) pathway inhibitors are clinically effective in treatment of basal cell carcinoma and medulloblastoma, but fail therapeutically or accelerate progression in treatment of endodermally derived colon and pancreatic cancers. In bladder, another organ of endodermal origin, we find that despite its initial presence in the cancer cell of origin Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression and decreases survival time. This cancer-restraining effect of Hh pathway activity is associated with stromal expression of BMP signals, which stimulate urothelial differentiation. Progression is dramatically reduced by pharmacological activation of BMP pathway activity with low-dose FK506, suggesting an approach to management of human bladder cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
47. Targeting the Wnt signaling pathways in pulmonary arterial hypertension.
- Author
-
de Jesus Perez V, Yuan K, Alastalo TP, Spiekerkoetter E, and Rabinovitch M
- Subjects
- Animals, Humans, Antihypertensive Agents pharmacology, Antihypertensive Agents therapeutic use, Hypertension, Pulmonary drug therapy, Hypertension, Pulmonary metabolism, Wnt Signaling Pathway drug effects
- Abstract
Pulmonary arterial hypertension (PAH) is a life-threatening disorder that is associated with elevated pulmonary pressures and right heart failure resulting from progressive loss and thickening of small pulmonary arteries. Despite their ability to improve symptoms, current therapies fail to prevent disease progression, leaving lung transplantation as the only therapy in end-stage PAH. To overcome the limitations of current therapies, there is an active search for disease-modifying agents capable of altering the natural history of, and improving clinical outcomes in, PAH. The Wnt signaling pathways have emerged as attractive treatment targets in PAH given their role in the preservation of pulmonary vascular homeostasis and the recent development of Wnt-specific compounds and biological therapies capable of modulating pathway activity. In this review, we summarize the literature describing the role of Wnt signaling in the pulmonary circulation and discuss promising advances in the field of Wnt therapeutics that could lead to novel clinical therapies capable of preventing and/or reversing pulmonary vascular pathology in patients with this devastating disease., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
48. Current clinical management of pulmonary arterial hypertension.
- Author
-
Zamanian RT, Kudelko KT, Sung YK, Perez VJ, Liu J, and Spiekerkoetter E
- Subjects
- Critical Care, Extracorporeal Membrane Oxygenation, Familial Primary Pulmonary Hypertension, Heart-Assist Devices, Humans, Hypertension, Pulmonary classification, Hypertension, Pulmonary diagnosis, Lung Transplantation, Practice Guidelines as Topic, Referral and Consultation, Hypertension, Pulmonary therapy
- Abstract
During the past 2 decades, there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality; yet, none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, and the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of patients with PAH have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based, and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this article, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure and a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field., (© 2014 American Heart Association, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
49. Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension.
- Author
-
Sawada H, Saito T, Nickel NP, Alastalo TP, Glotzbach JP, Chan R, Haghighat L, Fuchs G, Januszyk M, Cao A, Lai YJ, Perez Vde J, Kim YM, Wang L, Chen PI, Spiekerkoetter E, Mitani Y, Gurtner GC, Sarnow P, and Rabinovitch M
- Subjects
- Adolescent, Adult, Animals, Bone Morphogenetic Protein Receptors, Type II antagonists & inhibitors, Bone Morphogenetic Protein Receptors, Type II genetics, Case-Control Studies, Child, Endothelial Cells metabolism, Eukaryotic Initiation Factor-2 metabolism, Familial Primary Pulmonary Hypertension, Female, Humans, Hypertension, Pulmonary genetics, Hypertension, Pulmonary metabolism, MAP Kinase Signaling System, Macrophages metabolism, Macrophages pathology, Male, Mice, Mice, Inbred C57BL, Middle Aged, Myocytes, Smooth Muscle metabolism, Protein Biosynthesis, Protein Phosphatase 1 metabolism, Pulmonary Artery metabolism, Pulmonary Artery pathology, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering genetics, Rats, Rats, Sprague-Dawley, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Young Adult, Bone Morphogenetic Protein Receptors, Type II deficiency, Granulocyte-Macrophage Colony-Stimulating Factor biosynthesis, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Hypertension, Pulmonary etiology
- Abstract
Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34-PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)-positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.
- Published
- 2014
- Full Text
- View/download PDF
50. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension.
- Author
-
Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Haghighat R, Chan R, Haghighat L, de Jesus Perez V, Wang L, Reddy S, Zhao M, Bernstein D, Solow-Cordero DE, Beachy PA, Wandless TJ, Ten Dijke P, and Rabinovitch M
- Subjects
- Animals, Apoptosis, Bone Morphogenetic Protein 4 physiology, Bone Morphogenetic Protein Receptors, Type II genetics, Cell Hypoxia, Cell Line, Tumor, Cell Proliferation, Endothelial Cells drug effects, Endothelium, Vascular pathology, Endothelium, Vascular physiopathology, High-Throughput Screening Assays, Humans, Hypertension, Pulmonary metabolism, Hypertension, Pulmonary pathology, Inhibitor of Differentiation Protein 1 genetics, Inhibitor of Differentiation Protein 1 metabolism, Male, Mice, Mice, Knockout, Microvessels pathology, Neointima drug therapy, Neointima metabolism, Neointima pathology, Pulmonary Artery pathology, Rats, Rats, Sprague-Dawley, Signal Transduction, Smad Proteins metabolism, Tacrolimus Binding Protein 1A metabolism, Bone Morphogenetic Protein Receptors, Type II metabolism, Endothelial Cells physiology, Hypertension, Pulmonary drug therapy, Tacrolimus pharmacology
- Abstract
Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.