MicroRNA-30c Mitigates Hypercholesterolemia and Atherosclerosis in Mice

Abstract

High plasma cholesterol levels are found in several metabolic disorders and their reductions are advocated to reduce risk of atherosclerosis. A way to lower plasma lipids is to curtail lipoprotein assembly and secretion; however, this is asscociated with steatosis. Previously, we showed that lentiviral mediated hepatic expression of miR-30 reduces plasma cholesterol and atherosclerosis in mice. Since lentiviral delivery of miR-30c in humans for therapeutic purposes may pose several challenges and given the rapid progress of miRs from discovery to their potential development as a novel class of therapeutics, we hypothesized that a stabilized analogue of miR-30c (“mimic”) can replace viral delivery and be a suitable agent to lower hypercholesterolemia and atherosclerosis in male and female mice. To test this hypothesis, we complexed the synthetic miR-30c mimic with lipid emulsions and injected intravenously into mice placed on a Western diet to induce hyperlipidemia. Here, we show for the first time that weekly injections of a miR-30c mimic elevates hepatic miR-30c levels. This treatment results in sustained reductions in plasma cholesterol levels in Western diet-fed WT and Apoe−/− mice. The effect of miR-30c was dose dependent and the maximum effect on plasma cholesterol was observed 6 days after each injection. Further, we show that weekly injections of a miR-30c mimic also reduces atherosclerosis in Western diet-fed Apoe−/− mice. These reductions in plasma cholesterol and atherosclerosis were not accompanied with hepatic lipid accumulation or increases in plasma ALT, AST and CK, indicating that the miR-30c mimic was not causing hepatic steatosis or any obvious liver and muscle injury. To investigate more comprehensive role of miR-30c, we tested whether it can reduce plasma cholesterol and atherosclerosis in additional mouse models besides Western diet-induced hyperlipidemic mice. We found that miR-30c mimic significantly and safely lowers plasma cholesterol and atherosclerosis in Ldlr-deficient mice (Ldlr−/−), suggesting it a potential therapeutic modality for homozygous familial hypercholesterolemia (HoFH). Moreover, it dampens hypercholesterolemia in chow-fed type 2 diabetic and hypercholesterolemic ob/ob and db/db mice. However, it had no effect on plasma cholesterol in chow-fed STZ-induced diabetic and WT mice. Thus, these studies provide further proof of concept that miR-30c mimic could be developed into a safe, long-lasting and effective therapeutic agent for mitigating hypercholesterolemia in HoFH patients and in other hypercholesterolemic patients in general independent of the origin of hypercholesterolemia.