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Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies

ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin a5b1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin a5b1 or depletion of the a5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that α5β1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider α5β1 integrin inhibition as a promising therapy for pulmonary hypertension

ORGANISM(S): Homo sapiens

PROVIDER: GSE277556 | GEO | 2024/12/31

REPOSITORIES: GEO

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Characterization of DNA methylation changes associated with lung and right ventricle dysfunction in pulmonary hypertension

Project description:Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with pulmonary arteries remodeling and right ventricle (RV) dysfunction. Epigenetic dysregulation, including altered DNA methylation, promotes PAH. However, the DNA methylation changes associated with PAH and their functional consequences on transcriptomic reprogramming remain unexplored in human PAH RV and lungs. We conducted an exploratory study in human lung and RV samples to characterize the DNA methylome and transcriptomic changes associated with PAH in both organs. Impaired DNA methylation landscape observed in PAH lungs and RV correlates with adverse pulmonary vascular remodeling, RV fibrosis, and markers of disease severity (e.g. NT-proBNP). PAH differentially methylated genes and differentially expressed transcripts regulate biological functions related to inflammation, fibrosis, heart contraction, blood vessel development. Moreover, we observed substantial lung/RV transcriptomic and methylomic changes overlap in PAH. Thus, PAH is associated with specific DNA methylation changes associated with the disease severity.

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Comprehensive transcriptome analysis of heart tissues in the sugen/hypoxia rats with/without treatment of chrysin

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Pharmacological inhibition of G9a ameliorates pulmonary vascular remodeling in PAH

Project description:Background:Pulmonary arterial hypertension (PAH) is a severe condition characterized by progressive vascular remodeling of small pulmonary arteries (PAs) causing sustained elevation of PA pressure, right ventricular failure and death. Similar to cancer cells, PA smooth muscle cells (PASMCs), which play a key role in pulmonary vascular remodeling, have adopted multiple mechanisms to sustain their survival and proliferation in the presence of stress. The histone methyltransferase G9a has been shown to exert oncogenic effects and to serve as a buffer against an exaggerated transcriptional response. Therefore, we hypothesized that G9a up-regulation in PAH plays a pivotal role in pulmonary vascular remodeling by maintaining the abnormal phenotype of PAH-PASMCs. Methods: G9alevels were measured in PAs and isolated PASMCs of PAH patients and animal models. Selective G9a pharmacological inhibitors were used in human PAH-PASMCs and in rodent PAH models (i.e.Fawn-Hooded rats and Sugen/Hypoxia-exposed mice). Results: We present evidence of increased expression of G9a in PASMCs from PAH patients as well as in remodeled PAs from animal models. We found that pharmacological inhibition of G9a activity using BIX01294 and UNC0642significantly reduces the prosurvival and proproliferative potentials of cultured PAH-PASMCs. Using RNA sequencing, further exploration revealed that G9a promotes extracellular matrix production and affords protection against the negative effects of an overactive stress response. Finally, we found that therapeutic treatment with BIX01294 reduced pulmonary vascular remodeling and lowered mean PA pressure in Fawn-Hooded rats. Treatment of Sugen/hypoxia-challenged mice with BIX01294 also improved pulmonary hemodynamics and right ventricular function. Conclusions:These findings suggest that G9a inhibition may represent a new therapeutic approach in PAH.

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RNA-seq to characterize estrogen receptor alpha mutation in the female rat right ventricle with pressure overload

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2014-11-14 | E-GEOD-53408 | biostudies-arrayexpress

Fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension [bulk RNA-seq]

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2015-12-04 | E-GEOD-70456 | biostudies-arrayexpress

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