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Implication of EZH2 in the hyper-proliferative and apoptosis-resistant phenotype of pulmonary artery smooth muscle cells in PAH: a transcriptomic and proteomic approach

ABSTRACT: The aim of this study was to determine whether EZH2 represents a new factor critically involved in the cancer-like phenotype of PAH-PASMCs. We found that EZH2 is overexpressed in human lung tissues and isolated PASMCs from PAH patients compared to controls as well as in two animal models mimicking the disease. Through loss- and gain-of-function approaches, we showed that EZH2 promotes PAH-PASMC proliferation and survival. By combining quantitative transcriptomic and proteomic approaches in PAH-PASMCs subjected or not to EZH2 knockdown, we found that inhibition of EZH2 downregulates many factors involved in cell cycle progression, including E2F targets, and contributes to maintain energy production. Notably, we found that EZH2 promotes expression of several nuclear-encoded components of the mitochondrial translation machinery and TCA cycle genes. Overall, this study provides evidence that, by overexpressing EZH2, PAH-PASMCs remove the physiological breaks that normally restrain their proliferation and susceptibility to apoptosis and suggests that EZH2 or downstream factors may serve as therapeutic targets to combat pulmonary vascular remodeling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166996 | GEO | 2021/04/14

REPOSITORIES: GEO

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