MicroRNA-205-5p Promotes Unstable Atherosclerotic Plaque Formation In Vivo.

Abstract

Atherosclerosis is a narrowing of the arteries caused by plaque buildup. MicroRNAs (miRNAs) have been proposed to participate in the pathogenesis of atherosclerosis. Here, we aimed to investigate miR-205-5p's role in promoting atherosclerotic progression. Knock-in (KI) mice with human/murine miR-205-5p within the murine host gene for miR-205 (MIR205HG) were crossed with apolipoprotein E knockout (Apoe-/-) mice. This miR-205KI Apoe-/- murine model was employed to study the impact of miR-205-5p in Apoe-/- mice susceptible to atherosclerotic plaque formation. miR-205KI Apoe-/-mice developed larger, more unstable plaques relative to their Apoe-/- counterparts (0.45 vs. 0.26mm2, P < 0.001). miR-205KI Apoe-/- mice exhibited lower serum levels of high-density lipoprotein cholesterol (HDL-C) (5.18 vs. 19.31mg/dL, P < 0.001) and triglycerides (32.79 vs. 156.76mg/dL, P < 0.001) with system-wide reversal of cholesterol transport. Macrophages derived from miR-205KI Apoe-/- mice exhibited ~ 20% lowered cholesterol efflux capability with enhanced pro-inflammatory gene expression through lipid raft formation. Bone marrow transplantation demonstrated that bone marrow (BM) donor cells with miR-205-5pKI simulated plaque formation independent of the recipients' miR-205-5p status. miR-205-5p encourages unstable atherogenesis in vivo. miR-205-5p also adversely influences lipid metabolism and promotes a pro-inflammatory macrophage phenotype. Our findings advocate miR-205-5p as a potential therapeutic target for combating unstable atherogenesis.