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Background <p>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.</p> Methods <p>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.</p> Results <p>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).</p> Conclusion <p>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.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月27日

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  • Zongbin Li,
  • Miao Zhao,
  • Shanshan Ma,
  • Shuyu Lei

摘要

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.