Signal Transducers and Activators of Transcription-3/Pim1 Axis Plays a Critical Role in the Pathogenesis of Human Pulmonary Arterial Hypertension

This prospective cohort study is to verify the hypothesis that the balance of Th17 and Treg cells frequencies in the peripheral circulation is disturbed in patients with varying degrees of connective tissue diseases-associated pulmonary arterial hypertension (CTD-aPAH) and to prove the influence of Th17/Treg imbalance on prognosis. We detected the frequencies and absolute counts of Th17 and Treg cells and related serum cytokines secretion and expressions of key transcription factors in 117 patients with connective tissue diseases (CTD), 53 patients with CTD-aPAH, and 48 healthy volunteers. Moreover, the median value according to levels of Th17/Treg ratios in patients with CTD-aPAH was chosen as basis of group division for survival analysis. CTD-aPAH patients revealed significant increase in peripheral Th17 cells, Th17-related cytokines, and RORγt mRNA levels. They also presented a significant decrease in Treg cells, Treg-related cytokines, and Foxp3 mRNA levels as compared with CTD patients and healthy controls. More importantly, the Th17/Treg ratio was significantly related to the severity and prognosis of CTD-aPAH. This study indicated that the Th17/Treg axis disorder plays a critical role in CTD-aPAH. Furthermore, the dynamic balance between Th17 and Treg cells was likely to influence prognosis of patients with CTD-aPAH.

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Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

European Respiratory Review ◽

10.1183/16000617.0093-2017 ◽

2017 ◽

Vol 26 (146) ◽

pp. 170093 ◽

Cited By ~ 30

Author(s):

Anna R. Hemnes ◽

Marc Humbert

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Critical Role ◽

Fatal Disease ◽

Treatment Regimens ◽

Cellular Processes ◽

Considerable Research ◽

Pulmonary Arterial ◽

Target Alternative

The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets.

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Critical Role for the Advanced Glycation End‐Products Receptor in Pulmonary Arterial Hypertension Etiology

Journal of the American Heart Association ◽

10.1161/jaha.112.005157 ◽

2013 ◽

Vol 2 (1) ◽

Cited By ~ 60

Author(s):

Jolyane Meloche ◽

Antony Courchesne ◽

Marjorie Barrier ◽

Sophie Carter ◽

Malik Bisserier ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Advanced Glycation End Products ◽

Critical Role ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products ◽

Pulmonary Arterial

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Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

Pulmonary Circulation ◽

10.1177/2045893217741429 ◽

2017 ◽

Vol 8 (1) ◽

pp. 204589321774142 ◽

Cited By ~ 12

Author(s):

Valerie Nadeau ◽

Francois Potus ◽

Olivier Boucherat ◽

Renee Paradis ◽

Eve Tremblay ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

Skeletal Muscles ◽

Cell Metabolism ◽

Critical Role ◽

Capillary Density ◽

Pulmonary Hemodynamics ◽

Pulmonary Arterial

Dysregulated metabolism and rarefaction of the capillary network play a critical role in pulmonary arterial hypertension (PAH) etiology. They are associated with a decrease in perfusion of the lungs, skeletal muscles, and right ventricle (RV). Previous studies suggested that endothelin-1 (ET-1) modulates both metabolism and angiogenesis. We hypothesized that dual ETA/ETB receptors blockade improves PAH by improving cell metabolism and promoting angiogenesis. Five weeks after disease induction, Sugen/hypoxic rats presented severe PAH with pulmonary artery (PA) remodeling, RV hypertrophy and capillary rarefaction in the lungs, RV, and skeletal muscles (microCT angiogram, lectin perfusion, CD31 staining). Two-week treatment with dual ETA/ETB receptors antagonist macitentan (30 mg/kg/d) significantly improved pulmonary hemodynamics, PA vascular remodeling, and RV function and hypertrophy compared to vehicle-treated animals (all P = 0.05). Moreover, macitentan markedly increased lung, RV and quadriceps perfusion, and microvascular density (all P = 0.05). In vitro, these effects were associated with increases in oxidative phosphorylation (oxPhox) and markedly reduced cell proliferation of PAH-PA smooth muscle cells (PASMCs) treated with macitentan without affecting apoptosis. While macitentan did not affect oxPhox, proliferation, and apoptosis of PAH–PA endothelial cells (PAECs), it significantly improved their angiogenic capacity (tube formation assay). Exposure of control PASMC and PAEC to ET-1 fully mimicked the PAH cells phenotype, thus confirming that ET-1 is implicated in both metabolism and angiogenesis abnormalities in PAH. Dual ETA/ETB receptor blockade improved the metabolic changes involved in PAH-PASMCs’ proliferation and the angiogenic capacity of PAH-PAEC leading to an increased capillary density in lungs, RV, and skeletal muscles.

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Saracatinib and Dasatinib Fail To Prevent Heritable Pulmonary Arterial Hypertension

10.1101/345447 ◽

2018 ◽

Author(s):

Reid W. D’Amico ◽

Santhi Gladson ◽

Sheila Shay ◽

Courtney Copeland ◽

James D. West

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Tyrosine Kinases ◽

Critical Role ◽

Mutant Mice ◽

Wild Type ◽

C Terminus ◽

Pulmonary Arterial ◽

The Right ◽

Heritable Pulmonary Arterial Hypertension

AbstractEvidence suggests that the deregulation of SRC Family Kinases may play a role in the development of heritable pulmonary arterial hypertension, associated with BMPR2 mutations. The truncated c-terminus of the BMPR2 protein is known to increase the phosphorylation and downstream activity of SRC tyrosine kinases. To test the hypothesis that the inhibition of SRC can prevent heritable PAH due to a BMPR2 mutation, we exposed BMPR2 mutant mice to SRC inhibitors, saracatinib and dasatinib, to block the SRC activation caused by the BMPR2 mutation. Saracatinib and dasatinib failed to prevent the development of PAH in BMPR2 mutant mice. Increased pressure in the right ventricle was not normalized and muscularization of large blood vessels was not reduced when compared to wild type mice. Inhibiting SRC’s phosphorylation does not prevent heritable PAH, and thus supports evidence that SRC’s aberrant localization and trafficking in PAH plays a more critical role in disease development.

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Abstract 13932: Lung-targeted Sin3a Gene Therapy as a Promising Strategy to Restore Bmpr2 Expression in Pulmonary Arterial Hypertension

Circulation ◽

10.1161/circ.142.suppl_3.13932 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Malik Bisserier ◽

Prabhu Mathiyalagan ◽

Yassine Abdeldjebbar ◽

Shihong Zhang ◽

Firas Elmastour ◽

...

Keyword(s):

Gene Therapy ◽

Cell Proliferation ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Methylation Level ◽

Critical Role ◽

Methylation Status ◽

Pulmonary Arterial

Background: Pulmonary arterial hypertension (PAH) is a fatal lung disease of multifactorial etiology, with no curative treatment. Several studies have previously suggested that hypermethylation of the BMPR2 promoter may be associated with gene repression and disease progression. However, the underlying mechanisms have yet to be discovered. Sin3A/B (Switch-Independent 3) plays a critical role in the transcriptional regulation of genes through various epigenetic mechanisms. Here, we investigated for the first time the role of SIN3a in the regulation of BMPR2 methylation and expression in PAH. Methods: Expression of SIN3a was analyzed by qRT-PCR and western blot in lung tissues from PAH patients and rodent models of PAH. Using a gain- and loss-of-function approach, we investigated the role of SIN3a on cell proliferation (BrdU assay) and migration (Boyden chamber assay), and BMPR2 levels in primary human pulmonary arterial smooth muscle cells (hPASMC) and endothelial cells (hPAEC). The methylation level was analyzed by MS-PCR. The therapeutic potential of SIN3a was tested in vivo in the Sugen/Hypoxia (SuHx) mouse and monocrotaline (MCT) rat models of PAH using an adeno-associated virus 1 encoding human SIN3a. Results: We found a significant downregulation of SIN3a expression in the lung samples from PAH patients, SuHx mice, and MCT rats. In hPASMC and hPAEC, our results showed that SIN3a inhibits cell proliferation, migration, and upregulates BMPR2 through two distinct pathways. In hPASMC, our data showed that SIN3a upregulates BMPR2 expression by inhibiting the methylation level of the BMPR2 promoter. In hPAEC, SIN3a restored BMPR2 expression independently of the methylation status by upregulating the FOXK2 transcription factor. In vivo , our results showed that restoring SIN3a expression by gene therapy significantly decreased MCT- and SuHx-induced PAH as illustrated by decreased vascular and RV remodeling, hypertrophy, PAP and RVSP. Conclusions: Altogether, our study revealed that SIN3a plays a critical role in the regulation of BMPR2 expression by modulating the lung epigenetic landscape. Additionally, our study identifies lung-targeted SIN3a gene therapy as a new promising therapeutic strategy for treating PAH patients.

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Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension

European Respiratory Journal ◽

10.1183/13993003.00773-2015 ◽

2016 ◽

Vol 48 (4) ◽

pp. 1137-1149 ◽

Cited By ~ 38

Author(s):

Swati Dabral ◽

Xia Tian ◽

Baktybek Kojonazarov ◽

Rajkumar Savai ◽

Hossein Ardeschir Ghofrani ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Therapeutic Option ◽

Critical Role ◽

Systolic Pressure ◽

Ventricular Systolic Pressure ◽

Secretase Inhibitor ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterised by excessive pulmonary vascular remodelling involving deregulated proliferation of cells in intima, media as well as adventitia. Pulmonary arterial endothelial cell (PAEC) hyperproliferation and survival underlies the endothelial pathobiology of the disease.The indispensable involvement of Notch1 in the arterial endothelial phenotype and angiogenesis provides intriguing prospects for its involvement in the pathogenesis of PAH.We observed an increased expression of Notch1 in lungs of idiopathic PAH (IPAH) patients and hypoxia/SU5416 (SUHx) rats compared with healthy subjects. In vitro loss- and gain-of-function studies demonstrated that Notch1 increased proliferation of human PAECs (hPAECs) via downregulation of p21 and inhibited apoptosis via Bcl-2 and Survivin. Inhibition of Notch signalling using the γ-secretase inhibitor dibenzazepine dose-dependently decreased proliferation and migration of hPAECs. Notably, Notch1 expression and transcriptional activity were increased under hypoxia in hPAECs and knockdown of Notch1 inhibited hypoxia-induced proliferation of the cells. Furthermore, in vivo treatment with a γ-secretase inhibitor (AMG2008827) significantly reduced the right ventricular systolic pressure and right heart hypertrophy in SUHx rats.Here, we conclude that Notch1 plays a critical role in PAH and Notch inhibitors may be a promising therapeutic option for PAH.

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Critical Role Of The Receptor Of Advanced Glycation Endproducts/Peroxisome Proliferator-Activated Receptor Gamma Axis In Pulmonary Arterial Hypertension

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a6802 ◽

2012 ◽

Author(s):

Jolyane Meloche ◽

Marjorie Barrier ◽

Audrey Courboulin ◽

Malik Bisserier ◽

Steeve Provencher ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Advanced Glycation Endproducts ◽

Critical Role ◽

Peroxisome Proliferator ◽

Advanced Glycation ◽

Peroxisome Proliferator Activated Receptor ◽

Glycation Endproducts ◽

Pulmonary Arterial

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Identification of novel rare sequence variation underlying heritable pulmonary arterial hypertension

10.1101/185272 ◽

2017 ◽

Author(s):

Stefan Gräf ◽

Matthias Haimel ◽

Marta Bleda ◽

Charaka Hadinnapola ◽

Laura Southgate ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Transforming Growth Factor ◽

Rare Variants ◽

Critical Role ◽

Transforming Growth Factor Β ◽

Negative Control ◽

Morphogenetic Protein ◽

Pulmonary Arterial ◽

Heritable Pulmonary Arterial Hypertension

AbstractPulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie most heritable forms of PAH. Since the missing heritability likely involves genetic variation confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses revealed significant overrepresentation of rare variants in novel genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We provide evidence for familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, led to reduced secretion from transfected cells. In addition, we identified pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings provide new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

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