LncRNA 34962 drives pulmonary vascular remodeling in pulmonary hypertension due to left heart disease through the miR-3575/cMYC/TERT signaling axis.

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 vivo, AAV9-mediated lncRNA 34962 knockdown attenuated pulmonary vascular remodeling, reduced right ventricular systolic pressure (RVSP) and left atrial pressure (LAP), and alleviated ventricular hypertrophy in PH-LHD rats.

CONCLUSIONS

LncRNA 34962 promotes pulmonary vascular remodeling in PH-LHD through the miR-3575-cMYC-TERT signaling axis, supporting its therapeutic potential in PH-LHD.