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

摘要

Purpose 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. Methods 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. Results miR-205KI Apoe(-/-)mice developed larger, more unstable plaques relative to their Apoe(-/-) counterparts (0.45 vs. 0.26 mm(2), P < 0.001). miR-205KI Apoe(-/-) mice exhibited lower serum levels of high-density lipoprotein cholesterol (HDL-C) (5.18 vs. 19.31 mg/dL, P < 0.001) and triglycerides (32.79 vs. 156.76 mg/dL, P < 0.001) with system-wide reversal of cholesterol transport. Macrophages derived from miR-205KI Apoe(-/-) mice exhibited similar to 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. Conclusions 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.