3 years ago

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

Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis
Ángel Baldán, Manuel Mayr, Alberto Canfrán-Duque, Noemi Rotllan, Carlos Fernández-Hernando, David A. Ford, Nathan L. Price, Jack Moen, Noemi Arias, Yajaira Suárez, Paramita Pati, Xinbo Zhang


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.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31455-9

DOI: 10.1016/j.celrep.2017.10.023

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