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Cell Rep. 2017 Oct 31;21(5):1317-1330. doi: 10.1016/j.celrep.2017.10.023.

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

Author information

1
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, and Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
3
King's British Heart Foundation Centre, King's College London, London WC2R 2LS, UK.
4
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, and Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: carlos.fernandez@yale.edu.

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.

KEYWORDS:

Atherosclerosis; HDL-C; cholesterol; metabolism; miR-33

PMID:
29091769
PMCID:
PMC5687841
DOI:
10.1016/j.celrep.2017.10.023
[Indexed for MEDLINE]
Free PMC Article

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