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