RhoA accelerates atherosclerosis progression by interacting with Hspa5.

Abstract

RhoA has been demonstrated to play a role in atherosclerosis (AS); however, its regulatory mechanisms remain poorly characterized. This study aimed to investigate the function of RhoA in AS and elucidate its underlying mechanisms. An AS mouse model was established via a high-fat diet, and the role of RhoA was assessed by administering adeno-associated viruses. Mouse aortic vascular smooth muscle cells (MOVAS) were exposed to oxidized low-density lipoprotein (ox-LDL), and cellular phenotypes were analyzed using cell counting kit-8 assays, Transwell migration assays, transmission electron microscopy, and western blotting. The interaction between RhoA and Hspa5 was investigated through bioinformatic analysis, co-immunoprecipitation, and immunofluorescence. Results revealed that RhoA was highly upregulated in AS mice and predominantly localized in the smooth muscle layer of the aortic root. Knockdown of RhoA or inhibit its activity suppressed the viability, migration, invasion, and mitophagy of ox-LDL-treated MOVAS cells in vitro, and reduced plaque formation and inflammatory responses in AS mice. Furthermore, Hspa5 was found to interact with RhoA, with its expression positively correlated to RhoA levels. Overexpression of Hspa5 counteracted the inhibitory effects of RhoA silencing on cellular behaviors in ox-LDL-stimulated cells in vitro and plaque lesions and inflammation responses in vivo. Collectively, RhoA promotes vascular smooth muscle cell migration, invasion, and mitophagy via interaction with Hspa5, thereby exacerbating AS progression. These findings highlight RhoA as a potential therapeutic target for AS treatment.