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.

BACKGROUND: Pulmonary 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. METHODS: circRNA 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. RESULTS: circNLRP12 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). CONCLUSION: Our 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.