MicroRNA let-7g alleviates atherosclerosis via the targeting of LOX-1 in vitro and in vivo

Abstract

Atherosclerosis is a chronic arterial disease and the leading cause of stroke and myocardial infarction. MicroRNAs (miRNAs or miRs) have been reported to act as essential modulators during the progression of atherosclerosis. Although miR-let-7g has been demonstrated to contribute to maintaining endothelial function and vascular homeostasis, it is not known whether miR-let-7g exerts a therapeutic effect on experimental atherosclerosis. The aim of this study was to investigate the effects of miR-let-7g on atherosclerosis in vivo and in vitro and to explore its underlying mechanisms. Data from our study showed that exogenous lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1 or OLR1) overexpression resulted in the significant promotion of proliferation and migration of human aortic smooth muscle cells (ASMCs), whereas such changes induced by LOX-1 were obviously suppressed by transfection of miR-let-7g. We later confirmed that LOX-1 is a potential target of miR-let-7g, and miR-let-7g markedly inhibited LOX-1 expression in ASMCs by directly binding to the 3' untranslated region of LOX-1. Furthermore, in a hyperlipidemic apolipoprotein E knockout (ApoE-/-) mouse model, intravenous delivery of miR-let-7g mimics obviously attenuated high-fat diet-induced neointima formation and atherosclerotic lesions, accompanied by the significant downregulation of LOX-1, which was consistent with the effect of miR-let-7g on ASMCs. Taken together, our data revealed that miR-let-7g exhibits anti-atherosclerotic activity, at least partially by targeting the LOX-1 signaling pathway. This study suggests that miR-let-7g may be a therapeutic candidate for treating atherosclerosis, and provides novel insight into miRNA-based therapy for this disease.