title: Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis.
abstract: Plasma HDL levels have a protective role in atherosclerosis, yet clinical therapies to raise HDL levels have remained elusive. Recent advances in the understanding of lipid metabolism have revealed that miR-33, an intronic microRNA located within the SREBF2 gene, suppresses expression of the cholesterol transporter ABC transporter A1 (ABCA1) and lowers HDL levels. Conversely, mechanisms that inhibit miR-33 increase ABCA1 and circulating HDL levels, suggesting that antagonism of miR-33 may be atheroprotective. As the regression of atherosclerosis is clinically desirable, we assessed the impact of miR-33 inhibition in mice deficient for the LDL receptor (Ldlr-/- mice), with established atherosclerotic plaques. Mice treated with anti-miR33 for 4 weeks showed an increase in circulating HDL levels and enhanced reverse cholesterol transport to the plasma, liver, and feces. Consistent with this, anti-miR33-treated mice showed reductions in plaque size and lipid content, increased markers of plaque stability, and decreased inflammatory gene expression. Notably, in addition to raising ABCA1 levels in the liver, anti-miR33 oligonucleotides directly targeted the plaque macrophages, in which they enhanced ABCA1 expression and cholesterol removal. These studies establish that raising HDL levels by anti-miR33 oligonucleotide treatment promotes reverse cholesterol transport and atherosclerosis regression and suggest that it may be a promising strategy to treat atherosclerotic vascular disease.
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Katey J
authors.initials: KJ
authors.lastname: Rayner
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Sheedy
authors.forename: Christine C
authors.initials: CC
authors.lastname: Esau
authors.forename: Farah N
authors.initials: FN
authors.lastname: Hussain
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Temel
authors.forename: Saj
authors.initials: S
authors.lastname: Parathath
authors.forename: Janine M
authors.initials: JM
authors.lastname: van Gils
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Rayner
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Chang
authors.forename: Yajaira
authors.initials: Y
authors.lastname: Suarez
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Hernando
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008076:Cholesterol, HDL / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011897:Random Allocation; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D011973:Receptors, LDL