Anti-miR-33 therapy: when all that glitters is not gold
We, and others, discovered microRNA-33 in 2010 and demonstrated that it targets Abca1 and other lipid transporters. Interestingly, treatment of mice with antisense oligonucleotides was shown to significantly increase HDL-cholesterol. Because of these early studies, it was proposed that anti-miR-33 treatment might be anti-atherosclerotic. Therefore, we set out to determine the efficacy of long-term anti-miR-33 therapy on the progression of atherosclerosis in Ldlr-/- mice fed a high fat, high cholesterol diet. 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 HDL cholesterol after two weeks of treatment that was not sustained at the end of the experiment. Additionally, we found a significant increase in circulating triglycerides in anti-miR-33-treated mice, compared to controls. Finally, examination of atheromata revealed no significant changes in the size or composition of lesions between the three groups. We conclude that prolonged silencing of miR-33 fails to maintain elevated plasma HDL and does not prevent the progression of atherosclerosis in Ldlr -/- mice.