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

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 Apoemice developed larger, more unstable plaques relative to their Apoe counterparts (0.45 vs. 0.26 mm, 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 ~ 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.