Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis

Abstract

As an important regulator of macrophage cholesterol efflux and HDL biogenesis, miR-33 is a promising target for treatment of atherosclerosis, and numerous studies demonstrate that inhibition of miR-33 increases HDL levels and reduces plaque burden. However, important questions remain about how miR-33 impacts atherogenesis, including whether this protection is primarily due to direct effects on plaque macrophages or regulation of lipid metabolism in the liver. We demonstrate that miR-33 deficiency in Ldlr−/− mice promotes obesity, insulin resistance, and hyperlipidemia but does not impact plaque development. We further assess how loss of miR-33 or addition of miR-33b in macrophages and other hematopoietic cells impact atherogenesis. Macrophage-specific loss of miR-33 decreases lipid accumulation and inflammation under hyperlipidemic conditions, leading to reduced plaque burden. Therefore, the pro-atherogenic effects observed in miR-33-deficient mice are likely counterbalanced by protective effects in macrophages, which may be the primary mechanism through which anti-miR-33 therapies reduce atherosclerosis. miR-33a and miR-33b, the miR-33 family of miRNAs, are important regulators of reverse cholesterol transport and atherosclerosis. Price et al. have developed genetic models to explore the specific roles of miR-33a and miR-33b in atherosclerotic plaque formation. Their findings highlight both the utility and potential issues involved in anti-miR-33 therapies.