MicroRNA-451 inhibits vascular smooth muscle cell migration and intimal hyperplasia after vascular injury via Ywhaz/p38 MAPK pathway

Abstract Increasing evidence has indicated that intimal hyperplasia is a common event in the pathophysiology of many vascular diseases including atherosclerosis (AS). Recently, deregulated microRNAs (miRNAs) have been reported to be associated with the pathophysiology of AS. However, the biological function and regulatory mechanisms of miRNAs in intimal hyperplasia in AS remain largely unclear. The aim of this study was to investigate the effects of miRNAs on intimal hyperplasia and reveal the underlying mechanisms of their effects. Firstly, the model of rat vascular injury was successfully constructed in vivo . Then, the miRNAs expression profiles were analyzed by miRNA microarray. It was observed that miR-451 was significantly downregulated in injury carotid arteries. Subsequently, we investigated miR-451 function and found that upregulation of miR-451 by agomir-451 improves intimal thickening in rats following vascular injury. It was also observed that miR-451 was downregulated in the VSMCs following platelet-derived growth factor type BB (PDGF-BB) stimulation. The upregulation of miR-451 attenuated PDGF-BB-induced VSMCs injury, as evidenced by inhibition of proliferation, invasion and migration. Besides, overexpression of miR-451 blocked the activation of p38 MAPK signaling pathway in PDGF-BB treated VSMCs, as demonstrated by the downregulation of phosphorylated (p-) p38. In addition, Ywhaz, a positive regulator of p38 MAPK signaling pathway, was found to be a direct target of miR-451 in the VSMCs and this was validated using a luciferase reporter assay. Overexpression of Ywhaz partially abolished the inhibitory effects of miR-451 overexpression on PDGF-BB induced VSMCs injury. Collectively, these findings indicated that miR-451 protected intimal hyperplasia and PDGF-BB-induced VSMCs injury by Ywhaz/p38 MAPK pathway, and miR-451 may be considered as a potential therapeutic target in the treatment of AS.