Therapeutic Silencing of MicroRNA-33 Inhibits the Progression of Atherosclerosis in Ldlr −/− Mice—Brief Report

OBJECTIVE: To study the efficacy of anti-miRNA-33 therapy on the progression of atherosclerosis. APPROACH AND RESULTS: Ldlr(-/-) mice were injected subcutaneously with PBS, control, or anti-miR-33 oligonucleotides weekly and fed a Western diet for 12 weeks. At the end of treatment, the expression of miR-33 target genes was increased in the liver and aorta, demonstrating effective inhibition of miR-33 function. Interestingly, plasma high-density lipoprotein (HDL)-cholesterol was significantly increased in anti-miR-33-treated mice but only when they were fed a chow diet. However, HDL isolated from anti-miR-33-treated mice showed an increase cholesterol efflux capacity compared with HDL isolated from nontargeting oligonucleotide-treated mice. Analysis of atherosclerosis revealed a significant reduction of plaque size and macrophage content in mice receiving anti-miR-33. In contrast, no differences in collagen content and necrotic areas were observed among the 3 groups. CONCLUSIONS: Long-term anti-miR-33 therapy significantly reduces the progression of atherosclerosis and improves HDL functionality. The antiatherogenic effect is independent of plasma HDL-cholesterol levels.