Targeting CircNLRP12 attenuates hypoxia-induced pulmonary arterial smooth muscle cell dysfunction by sponging miR-107-5p and suppressing the ITGA2-mediated FAK/PI3K/AKT pathway.

backgroundPulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) drives lethal pulmonary vascular remodeling. While circular RNAs (circRNAs) are emerging as disease regulators, their functional roles in PAH-CHD remain unexplored.

methodscircRNA sequencing of peripheral blood from 5 PAH-CHD patients versus 5 congenital heart disease(CHD) controls identified dysregulated circRNAs. Functional validation utilized hypoxia-exposed human pulmonary arterial smooth muscle cells (hPASMCs) with circNLRP12 silencing (siRNA), complemented by luciferase assays, quantitative polymerase chain reaction (qPCR),Western blot, and phenotypic analyses.

resultscircNLRP12 was significantly upregulated in PAH-CHD patients and hypoxia-exposed hPASMCs. Functional studies demonstrated that circNLRP12 silencing markedly attenuated hypoxia-induced proliferation and migration while reversing apoptosis resistance in hPASMCs. Mechanistically, circNLRP12 acted as a molecular sponge for miR-107-5p, leading to increased integrin alpha 2 (ITGA2) expression and subsequent activation of the focal adhesion kinase/phosphoinositide 3-kinase/protein kinase B/hypoxia inducible factor-1α (FAK/PI3K/AKT/HIF-1α) signaling pathway, which ultimately promoted vascular remodeling through downstream effectors including vascular endothelial growth factor(VEGF) and α-Smooth Muscle Actin(α-SMA).

conclusionOur findings show that circNLRP12 promotes hPASMCs proliferation and dysfunction through a miR-107-5p/ITGA2 axis. As a novel biomarker and therapeutic target, it may serve as significant potential for guiding clinical interventions.