MiR‐629 regulates hypoxic pulmonary vascular remodelling by targeting FOXO3 and PERP

Abstract

Pulmonary arterial hypertension (PAH) is featured by the increase in pulmonary vascular resistance and pulmonary arterial pressure. Despite that abnormal proliferation and phenotypic changes in human pulmonary artery smooth muscle cells (HPASMCs) contributing to the pathophysiology of PAH, the underlying molecular mechanisms remain unclear. In the present study, we detected the expression of miR‐629 in hypoxia‐treated HPASMCs and explored the mechanistic role of miR‐629 in regulating HPASMC proliferation, migration and apoptosis. Hypoxia time‐dependently induced up‐regulation of miR‐629 and promoted cell viability and proliferation in HPASMCs. Treatment with miR‐629 mimics promoted HPASMCs proliferation and migration, but inhibited cell apoptosis; while knockdown of miR‐629 suppressed the cell proliferation and migration but promoted cell apoptosis in HPASMCs. The bioinformatics prediction revealed FOXO3 and PERP as downstream targets of miR‐629, and miR‐629 negatively regulated the expression of FOXO3 and PERP via targeting the 3’ untranslated regions. Enforced expression of FOXO3 or PERP attenuated the miR‐629 overexpression or hypoxia‐induced enhanced effects on HPASMC proliferation and proliferation, and the suppressive effects on HPASMC apoptosis. Furthermore, the expression of miR‐629 was up‐regulated, and the expression of FOXO3 and PERP mRNA was down‐regulated in the plasma from PAH patients when compared to healthy controls. In conclusion, the present study provided evidence regarding the novel role of miR‐629 in regulating cell proliferation, migration and apoptosis of HPASMCs during hypoxia.

Bioactivities and mechanisms of natural medicines in the management of pulmonary arterial hypertension

“…MicroRNAs (miRNAs), small non‐coding RNAs 21–23 nucleotides in length, have been reported to participate in many biological processes (e.g., cell proliferation, migration, invasion and apoptosis) [ 122 ]. For instance, microRNA-629 promotes PASMC proliferation and migration, suppresses apoptosis by downregulating the target of forkhead box O3 (FOXO3) and p53 apoptosis effector related to PMP‐22 (PERP) in hypoxia-induced PASMCs [ 123 ]. Another report also showed that overexpression of microRNA-150 relieved pulmonary fibrosis and collagen I in hypoxia-induced rats, and the specific mechanism is thought to occur through inhibition of the AKT/mTOR signalling pathway [ 124 ].…”

Role of endothelial microRNA-150 in pulmonary arterial hypertension

“…3C), likely to indicate a direct transcriptional regulatory effect. Increase in the expression of PTPMT1 and reduction in the expression of other gene regulators of vascular remodelling identified by RNAseq, SERPINE1 (Simone, Higgins et al, 2014), PERP (Zhao, Chen et al, 2019), DUSP5 (Chen, Zmuda et al, 2020), NOTCH3 (Li, Zhang et al, 2009) and c-myb (You, Mungrue et al, 2003) were validated by qPCR ( Fig. 3D and Appendix Figure S2).…”

Expression Profiles of Circular RNA in Aortic Vascular Tissues of Spontaneously Hypertensive Rats

“…FOXO3, as a transcriptional factor and important mediator, has been shown to contribute to the protective effects of cardiovascular fibrosis and ischemia-reperfusion (I/R) injury (34). miR-629 promoted cell proliferation, migration and apoptosis by targeting FOXO3 in vascular remodeling (35). The functions of miR-124 on hypertensive pulmonary fibroblast proliferation were mediated through FOXO3/cdk inhibitor cdkn1a signaling (36).…”