MicroRNA‐451 Protects against Atherosclerotic Plaque Formation by directly targeting Ras‐associated Protein 5a in Vascular Smooth Muscle Cells

Abstract

MicroRNA‐451 (miR‐451) modulates erythroid differentiation and human malignancy. However, its role in the regulation of vascular smooth muscle cell (VSMC) function in health and disease remains unclear. Using a combination of in vitro system and in vivo investigations on experimental animals and human clinical specimens to clarify the function of miR‐451 in VSMCs. In situ hybridization showed that miR‐451 was significantly expressed in VSMCs of the medial layer in diseased human coronary arteries. In vitro study, culturing VSMCs on fibrillar collagen increased miR‐451 level and led to low proliferative and anti‐inflammatory responses; these effects were diminished by anti‐miR‐451. We identified that Rab5a was targeted by miR‐451 to modulate VSMC proliferation and inflammation. In rat studies, overexpression of miR‐451 and lentivirus‐mediated Rab5a silencing markedly suppressed the neointima formation induced by balloon injury. The level of circulating miR‐451 of blood plasma in patients with coronary artery disease and apolipoprotein E knockout mice (ApoE‐/‐) fed with a high‐cholesterol diet was significantly lower than control group. Increase of circulating miR‐451 by tail vein injection with agomir‐451 in ApoE‐/‐ mice fed with a high‐cholesterol diet for three months decreased atherosclerotic lesion formation. Our findings indicate that miR‐451, by targeting Rab5a, inhibits VSMC proliferation and inflammation in cultured VSMCs in vitro and suppresses neointima formation in injured arteries in vivo.