Hypoxia-induced long non-coding RNA plasmacytoma variant translocation 1 upregulation aggravates pulmonary arterial smooth muscle cell proliferation by regulating autophagy via miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways.

The lncRNA PVT1 reportedly functions as a competing endogenous RNA (ceRNA) of miR-186 and miR-26b in different tissue types. In this study, we investigated the possible involvement of the miR-186/ Srf / Ctgf and miR-26b/ Ctgf signaling pathways in the pathogenesis of hypoxia-induced PAH. Expression of PVT1, miR-186, miR-26b, and Srf and Ctgf mRNAs were evaluated by real-time polymerase chain reaction. Protein expression of SRF, CTGF, LC3B-I, LC3B-II, and Beclin-I was evaluated using western blotting. The regulatory relationship between the lncRNA, miRNAs, and target mRNAs was explored using luciferase assays. Immunohistochemistry was used to evaluate the expression of SRF and CTGF in situ. MTT assay was performed to assess the proliferation of PASMCs. Exposure to hypoxia markedly altered the expression of PVT1, Srf, Ctgf , miR-186, and miR-26b in a rat model. MiR-186 binding sites in the sequences of Srf mRNA and PVT1 were confirmed by luciferase assays, indicating that miR-186 may interact with both PVT1 and Srf mRNA. Additionally, miR-26b binding sites were identified in the sequences of Ctgf mRNA and PVT1, suggesting that miR-26b may interact with both PVT1 and Ctgf mRNA. In line with this, we found that overexpression of PVT1 reduced expression of miR-26b and miR-186 but activated expression of Srf , Ctgf , LC3B-II, and Beclin-I. Upregulation of PVT1 by exposure to hypoxia promoted the expression of CTGF, leading to deregulation of autophagy and abnormal proliferation of PASMCs. Dysregulation of the miR-186/ Srf / Ctgf and miR-26b/ Ctgf signaling pathways may be involved in the pathogenesis of hypoxia-induced PASMCs. [Display omitted] • PVT1 could promote the progression of hypoxic pulmonary hypertension. • MiR-186 and miR-26b were dysregulated in the hypoxia-induced PASMCs and participated in the progression of HPH. • PVT1/miR-186/ Srf / Ctgf and PVT1/ miR -26b / Ctgf regulatory networks ultimately affected the proliferation of PASMCs through CTGF in the HPH model. [ABSTRACT FROM AUTHOR]