Hai-Rong Li, Guan-Liang Chen, Xiao-Li Fang, Xing-jiu Cai, Rong-Li Xu, Dong-Dong Li, Zhi-Wei Zhang
Southern Medical University. Hainan General Hospital and Hainan Affiliated Hospital of Hainan Medical University. Guangdong General Hospital.
China
American Journal of Hypertension
Am J Hypertens 2023;
DOI: 10.1093/ajh/hpad028
Abstract
Background: Uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the pathogenesis of pulmonary arterial hypertension (PAH). In this work, we defined the precise part of circ_0068481 in PASMC proliferation and migration induced by hypoxia. We hypothesized that circ_0068481 enhanced hypoxia-induced PASMC proliferation, invasion and migration through the miR-361-3p/KLF5 pathway.
Methods: Human PASMCs (hPASMCs) were exposed to hypoxic (3% O2) conditions. Circ_0068481, microRNA (miR)-361-3p and Krüppel-like factor 5 (KLF5) levels were gauged by qRT-PCR and western blot. Cell viability, proliferation, invasion and migration were detected by XTT, EdU incorporation, transwell and wound-healing assays, respectively. Dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to confirm the direct relationship between miR-361-3p and circ_0068481 or KLF5.
Results: Circ_0068481 expression was increased in the serum of PAH patients and hypoxia-induced hPASMCs. Downregulation of circ_0068481 attenuated hypoxia-induced promotion in hPASMC proliferation, invasion and migration. Circ_0068481 directly targeted miR-361-3p, and miR-361-3p downregulation reversed the inhibitory effects of circ_0068481 silencing on hypoxia-induced hPASMC proliferation, invasion and migration. KLF5 was a direct miR-361-3p target, and miR-361-3p upregulation mitigated hypoxia-induced hPASMC proliferation, invasion and migration by inhibiting KLF5 expression. Moreover, circ_0068481 induced KLF5 expression by binding to miR-361-3p in hypoxic hPASMCs.
Conclusion: Circ_0068481 knockdown ameliorated hypoxia-induced hPASMC proliferation, invasion and migration at least in part through the miR-361-3p/KLF5 axis.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
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