长链非编码RNA 34962通过miR-3575/cMYC/TERT信号轴，驱动左心病引发的肺动脉高压患者肺血管重构

Abstract

LncRNA 34962 is upregulated in pulmonary arteries and PASMCs in PH-LHD. • LncRNA 34962 promotes PASMC proliferation and migration via miR-3575/cMYC. • CMYC-driven TERT upregulation promotes telomerase activation in PH-LHD PASMCs. • TERT overexpression partially rescues the effects of cMYC knockdown in PASMCs. • AAV9-mediated lncRNA 34962 knockdown attenuates pulmonary vascular remodeling. Background Pulmonary hypertension due to left heart disease (PH-LHD) is the most prevalent form of pulmonary hypertension, characterized by pulmonary vascular remodeling driven by abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Although long non-coding RNAs (lncRNAs) regulate cardiovascular pathophysiology, their role in PH-LHD remains unclear. Methods PH-LHD was established by aortic banding. RNA sequencing (RNA-seq) revealed differentially expressed lncRNAs in the pulmonary vasculature. The roles of lncRNA 34962 in PASMC proliferation and migration were assessed through gain- and loss-of-function experiments and 5-ethynyl-2′-deoxyuridine (EdU) incorporation, Cell Counting Kit-8 (CCK-8), and wound-healing assays. The competitive endogenous RNA (ceRNA) mechanism was examined using dual-luciferase reporter assays and RNA fluorescence in situ hybridization (FISH) and RNA immunoprecipitation (RIP) analyses. Therapeutic potential was evaluated in vivo by intratracheal delivery of adeno-associated virus serotype 9 (AAV9)-mediated short hairpin RNA. Results LncRNA 34962 was upregulated in pulmonary arteries and PASMCs from PH-LHD rats. Its overexpression enhanced PASMC proliferation and migration, whereas its knockdown exerted inhibitory effects. Mechanistically, lncRNA 34962 sequestered miR-3575, thereby relieving miR-3575-mediated repression of cMYC. cMYC upregulation increased telomerase reverse transcriptase (TERT) expression and telomerase activation, sustaining cell-cycle progression and the proliferative and migratory capacity of PASMCs. In