Zongbin Li, Miao Zhao, Shanshan Ma, Shuyu Lei
Third People’s Hospital of Xinjiang Uygur Autonomous Region.
China
European Journal of Medical Research
Eur J Med Res 2025;
DOI: 10.1186/s40001-025-03586-0
Abstract
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.
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Genetic Factors Associated with Pulmonary Vascular Disease
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Potential Biomarkers Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes