Role of hsa_circ_0000280 in regulating vascular smooth muscle cell function and attenuating neointimal hyperplasia via ELAVL1

Abstract

AbstractThe pathological proliferation of cells in vascular smooth muscle underlies neointimal hyperplasia (NIH) development during atherosclerosis. Circular RNAs (circRNAs), which represent novel functional biomarkers and RNA-binding proteins, contribute to multiple cardiovascular diseases; however, their roles in regulating the vascular smooth muscle cell cycle remain unknown. Thus, we aimed to identify the roles of circRNAs in vascular smooth muscle during coronary heart disease (CHD). Through circRNA sequencing of CHD samples and human antigen R (ELAVL1) immunoprecipitation, we identified circRNAs that are associated with CHD and interact with ELAVL1. Our results suggested that the hsa_circ_0000280 associated with CHD inhibits cell proliferation and induces ELAVL1-dependent cell cycle arrest. Gain/loss-of-function experiments and assays in vivo indicated that hsa_circ_0000280 facilitates interactions between ELAVL1 and cyclin-dependent kinase suppressor 1 (CDKN1A) mRNA and stabilization of this complex and leads to cell cycle arrest at the G1/S checkpoint, inhibiting cell proliferation of vascular smooth muscle cells in vitro and NIH in vivo. Importantly, hsa_circ_0000280 reduced neointimal thickness and smooth muscle cell proliferation in vivo. Taken together, these findings reveal a novel pathway in which hsa_circ_0000280 facilitates the regulation of ELAVL1 on CDKN1A mRNA to inhibit NIH. Therefore, measuring and modulating their expression might represent a potential diagnostic or therapeutic strategy for CHD.