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Arterioscler Thromb Vasc Biol. 2017 Jun;37(6):1058-1067. doi: 10.1161/ATVBAHA.116.308916. Epub 2017 Apr 20.

microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis.

Author information

1
From the Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine (M.O., H.E., M.S.A., R.C.B., K.R., E.A.F., K.J.M.) and Division of Vascular Surgery, Department of Surgery (B.R.), New York University Medical Center; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Canada (R.S., K.J.R., J.P.P.); National Research Council of Canada, Ottawa, Ontario (R.S., J.P.P.); Departments of Medicine, Pathology and Cell Biology, Columbia University, New York (X.L., I.T.); and University of Ottawa Heart Institute, Ontario, Canada (K.J.R.).
2
From the Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine (M.O., H.E., M.S.A., R.C.B., K.R., E.A.F., K.J.M.) and Division of Vascular Surgery, Department of Surgery (B.R.), New York University Medical Center; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Canada (R.S., K.J.R., J.P.P.); National Research Council of Canada, Ottawa, Ontario (R.S., J.P.P.); Departments of Medicine, Pathology and Cell Biology, Columbia University, New York (X.L., I.T.); and University of Ottawa Heart Institute, Ontario, Canada (K.J.R.). kathryn.moore@nyumc.org.

Abstract

OBJECTIVE:

Defective autophagy in macrophages leads to pathological processes that contribute to atherosclerosis, including impaired cholesterol metabolism and defective efferocytosis. Autophagy promotes the degradation of cytoplasmic components in lysosomes and plays a key role in the catabolism of stored lipids to maintain cellular homeostasis. microRNA-33 (miR-33) is a post-transcriptional regulator of genes involved in cholesterol homeostasis, yet the complete mechanisms by which miR-33 controls lipid metabolism are unknown. We investigated whether miR-33 targeting of autophagy contributes to its regulation of cholesterol homeostasis and atherogenesis.

APPROACH AND RESULTS:

Using coherent anti-Stokes Raman scattering microscopy, we show that miR-33 drives lipid droplet accumulation in macrophages, suggesting decreased lipolysis. Inhibition of neutral and lysosomal hydrolysis pathways revealed that miR-33 reduced cholesterol mobilization by a lysosomal-dependent mechanism, implicating repression of autophagy. Indeed, we show that miR-33 targets key autophagy regulators and effectors in macrophages to reduce lipid droplet catabolism, an essential process to generate free cholesterol for efflux. Notably, miR-33 regulation of autophagy lies upstream of its known effects on ABCA1 (ATP-binding cassette transporter A1)-dependent cholesterol efflux, as miR-33 inhibitors fail to increase efflux upon genetic or chemical inhibition of autophagy. Furthermore, we find that miR-33 inhibits apoptotic cell clearance via an autophagy-dependent mechanism. Macrophages treated with anti-miR-33 show increased efferocytosis, lysosomal biogenesis, and degradation of apoptotic material. Finally, we show that treating atherosclerotic Ldlr-/- mice with anti-miR-33 restores defective autophagy in macrophage foam cells and plaques and promotes apoptotic cell clearance to reduce plaque necrosis.

CONCLUSIONS:

Collectively, these data provide insight into the mechanisms by which miR-33 regulates cellular cholesterol homeostasis and atherosclerosis.

KEYWORDS:

atherosclerosis; autophagy; hydrolysis; lipid droplets; macrophages

PMID:
28428217
PMCID:
PMC5494696
DOI:
10.1161/ATVBAHA.116.308916
[Indexed for MEDLINE]
Free PMC Article

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