Role of MiR-542-3p/Integrin-Linked Kinase/Myocardin Signaling Axis in Hypoxic Pulmonary Hypertension
Linqing Li, Weining Zhou, Qingrong Ji, Xianzhao Zhang, Ni Yang, Kaiyou Song, Shunpeng Hu, Cunfei Liu, Zhihong Ou, Fengwei Zhang, Yuda Wei, Jiantong Hou
https://doi.org/10.1002/pul2.70094
Abstract
Phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) under hypoxic conditions, which in turn causes increased proliferation and migration capacity, is an important pathological process in Hypoxic pulmonary hypertension (HPH). Although research on the phenotypic transition of PASMCs has been ongoing, little is known about the specific molecular mechanisms underlying this process. Integrin-linked kinase (ILK) is one of the genes essential for maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs). It has been shown that ILK is a target gene of MiR-542-3p, and overexpression of MiR-542-3p can promote apoptosis of osteosarcoma cells by downregulating the expression of ILK, and inhibit their cell proliferation, migration, and invasion. In this study we found that hypoxia upregulated MiR-542-3p expression, and MiR-542-3p mimics reduced ILK, Myocardin expression, and promote phenotypic transition in PASMCs. And, ILK was a direct target of MiR-542-3p in PASMCs. MiR-542-3p inhibitor reversed hypoxia-induced reduction of ILK and Myocardin expression in PASMCs, and phenotypic transition, proliferation, and migration of PASMCs. MiR-542-3p antagomir reversed hypoxia-induced pulmonary vascular remodeling and also reversed hypoxia-induced reduction in ILK, Myocardin expression, and phenotype transition in rat pulmonary arteries. Thus, our results suggest that hypoxia induced an increase in MiR-542-3p expression, which caused an increase in binding to ILK gene and negatively regulated ILK expression. This in turn, caused a decrease in Myocardin expression leading to phenotypic transition, proliferation, and increased migration of PASMCs, causing hypoxic pulmonary vascular remodeling and ultimately leading to HPH.