Anti-miR-33 therapy does not alter the progression of atherosclerosis in low-density lipoprotein receptor-deficient mice.

OBJECTIVE To determine the efficacy of long-term anti-miR-33 therapy on the progression of atherosclerosis in high-fat, high-cholesterol-fed Ldlr(-/-) mice. METHODS AND RESULTS Ldlr(-/-) mice received saline, or control or anti-miR-33 oligonucleotides once a week for 14 weeks. The treatment was effective, as measured by reduced levels of hepatic miR-33 and increased hepatic expression of miR-33 targets. Analysis of plasma samples revealed an initial elevation in high-density lipoprotein cholesterol after 2 weeks of treatment that was not sustained by the end of the experiment. Additionally, we found a significant increase in circulating triglycerides in anti-miR-33-treated mice, compared with controls. Finally, examination of atheromata revealed no significant changes in the size or composition of lesions between the 3 groups. CONCLUSIONS Prolonged silencing of miR-33 fails to maintain elevated plasma high-density lipoprotein cholesterol and does not prevent the progression of atherosclerosis in Ldlr(-/-) mice.