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PiRNA-63076 contributes to pulmonary arterial smooth muscle cell proliferation through acyl-CoA dehydrogenase.

ABSTRACT: Piwi-interacting RNAs (piRNAs) are thought to be germline-specific and to be involved in maintaining genome stability during development. Recently, piRNA expression has been identified in somatic cells in diverse organisms. However, the roles of piRNAs in pulmonary arterial smooth muscle cell (PASMC) proliferation and the molecular mechanism underlying the hypoxia-regulated pathological process of pulmonary hypertension are not well understood. Using hypoxic animal models, cell and molecular biology, we obtained the first evidence that the expression of piRNA-63076 was up-regulated in hypoxia and was positively correlated with cell proliferation. Subsequently, we showed that acyl-CoA dehydrogenase (Acadm), which is negatively regulated by piRNA-63076 and interacts with Piwi proteins, was involved in hypoxic PASMC proliferation. Finally, Acadm inhibition under hypoxia was partly attributed to DNA methylation of the Acadm promoter region mediated by piRNA-63076. Overall, these findings represent invaluable resources for better understanding the role of epigenetics in pulmonary hypertension associated with piRNAs.

SUBMITTER: Ma C

PROVIDER: S-EPMC7205801 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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piRNA-63076 contributes to pulmonary arterial smooth muscle cell proliferation through acyl-CoA dehydrogenase.

Ma Cui C Zhang Lixin L Wang Xiaoying X He Siyu S Bai June J Li Qian Q Zhang Min M Zhang Chen C Yu Xiufeng X Zhang Junting J Xin Wei W Li Yiying Y Zhu Daling D

Journal of cellular and molecular medicine 20200330 9

Piwi-interacting RNAs (piRNAs) are thought to be germline-specific and to be involved in maintaining genome stability during development. Recently, piRNA expression has been identified in somatic cells in diverse organisms. However, the roles of piRNAs in pulmonary arterial smooth muscle cell (PASMC) proliferation and the molecular mechanism underlying the hypoxia-regulated pathological process of pulmonary hypertension are not well understood. Using hypoxic animal models, cell and molecular bio ...[more]

PMID: 32227582

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Project description:RationalePulmonary arterial hypertension (PAH) is a rare progressive pulmonary vascular disorder associated with vascular remodeling and right heart failure. Vascular remodeling involves numerous signaling cascades governing pulmonary arterial smooth muscle cell (PASMC) proliferation, migration and differentiation. Glycogen synthase kinase 3beta (GSK3ß) is a serine/threonine kinase and can act as a downstream regulatory switch for numerous signaling pathways. Hence, we hypothesized that GSK3ß plays a crucial role in pulmonary vascular remodeling.MethodsAll experiments were done with lung tissue or isolated PASMCs in a well-established monocrotaline (MCT)-induced PAH rat model. The mRNA expression of Wnt ligands (Wnt1, Wnt3a, Wnt5a), upstream Wnt signaling regulator genes (Frizzled Receptors 1, 2 and secreted Frizzled related protein sFRP-1) and canonical Wnt intracellular effectors (GSK3ß, Axin1) were assessed by real-time polymerase chain reaction and protein levels of GSK3ß, phospho-GSK3ß (ser 9) by western blotting and localization by immunohistochemistry. The role of GSK3ß in PASMCs proliferation was assessed by overexpression of wild-type GSK3ß (WT) and constitutively active GSK3ß S9A by [(3)H]-thymidine incorporation assay.ResultsIncreased levels of total and phosphorylated GSK3ß (inhibitory phosphorylation) were observed in lungs and PASMCs isolated from MCT-induced PAH rats compared to controls. Further, stimulation of MCT-PASMCs with growth factors induced GSK3ß inactivation. Most importantly, treatment with the PDGFR inhibitor, Imatinib, attenuated PDGF-BB and FCS induced GSK3ß phosphorylation. Increased expression of GSK3ß observed in lungs and PASMC isolated from MCT-induced PAH rats was confirmed to be clinically relevant as the same observation was identified in human iPAH lung explants. Overexpression of GSK3ß significantly increased MCT-PASMCs proliferation by regulating ERK phosphorylation. Constitutive activation of GSK3ß (GSK3ß S9A, 9th serine replaced to alanine) inhibited MCT-PASMCs proliferation by decreasing ERK phosphorylation.ConclusionThis study supports a central role for GSK3ß in vascular remodeling processes and suggests a novel therapeutic opportunity for the treatment of PAH.

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PiRNA-63076 contributes to pulmonary arterial smooth muscle cell proliferation through acyl-CoA dehydrogenase.

Publications

piRNA-63076 contributes to pulmonary arterial smooth muscle cell proliferation through acyl-CoA dehydrogenase.

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