MicroRNA-145 Targeted Therapy Reduces Atherosclerosis

TLDR

MicroRNAs are essential posttranscriptional modulators of gene expression implicated in various chronic diseases. The study hypothesized that microRNA‑145, highly expressed in vascular smooth muscle cells, could regulate atherosclerosis and plaque stability, and tested this by treating ApoE(-/-) mice with an SMC‑specific microRNA‑145 lentivirus before a Western diet. The authors delivered the microRNA‑145 lentivirus under the SM22α promoter to ApoE(-/-) mice and then fed them a Western diet for 12 weeks. SMC‑targeted microRNA‑145 markedly reduced plaque size, increased fibrous cap and collagen, decreased necrotic core and macrophage content, and promoted a contractile VSMC phenotype, thereby enhancing plaque stability in ApoE(-/-) mice.

Abstract

MicroRNA are essential posttranscriptional modulators of gene expression implicated in various chronic diseases. Because microRNA-145 is highly expressed in vascular smooth muscle cells (VSMC) and regulates VSMC fate and plasticity, we hypothesized that it may be a novel regulator of atherosclerosis and plaque stability.Apolipoprotein E knockout mice (ApoE(-/-)) mice were treated with either a microRNA-145 lentivirus under the control of the smooth muscle cell (SMC)-specific promoter SM22α or a SM22α control lentivirus before commencing the Western diet for 12 weeks. The SMC-targeted microRNA-145 treatment markedly reduced plaque size in aortic sinuses, ascending aortas, and brachiocephalic arteries. It also significantly increased fibrous cap area, reduced necrotic core area, and increased plaque collagen content. Cellular plaque composition analyses revealed significantly less macrophages in ApoE(-/-) mice treated with the SMC-specific microRNA-145. These mice also demonstrated marked increases in calponin levels and α-smooth muscle actin-positive SMC areas in their atherosclerotic lesions. Furthermore, lentiviral delivery of microRNA-145 resulted in reduced KLF4 and elevated myocardin expression in aortas from ApoE(-/-) mice, consistent with an effect of microRNA-145 to promote a contractile phenotype in VSMC.VSMC-specific overexpression of microRNA-145 is a novel in vivo therapeutic target to limit atherosclerotic plaque morphology and cellular composition, shifting the balance toward plaque stability vs plaque rupture.