title: miR33 inhibition overcomes deleterious effects of diabetes mellitus on atherosclerosis plaque regression in mice.
abstract: BACKGROUND
  Diabetes mellitus increases cardiovascular disease risk in humans and remains elevated despite cholesterol-lowering therapy with statins. Consistent with this, in mouse models, diabetes mellitus impairs atherosclerosis plaque regression after aggressive cholesterol lowering. MicroRNA 33 (miR33) is a key negative regulator of the reverse cholesterol transport factors, ATP-binding cassette transporter A1 and high-density lipoprotein, which suggested that its inhibition may overcome this impairment.
  
  
  OBJECTIVE
  To assess the effects of miR33 inhibition on atherosclerosis regression in diabetic mice.
  
  
  RESULTS
  Reversa mice, which are deficient in the low-density lipoprotein receptor and in which hypercholesterolemia is reversed by conditional inactivation of the microsomal triglyceride transfer protein gene, were placed on an atherogenic diet for 16 weeks, then either made diabetic by streptozotocin injection or kept normoglycemic. Lipid-lowering was induced by microsomal triglyceride transfer protein gene inactivation, and mice were treated with anti-miR33 or control oligonucleotides. Although regression was impaired in diabetic mice treated with control oligonucleotides, anti-miR33 treatment decreased plaque macrophage content and inflammatory gene expression in these mice. The decreased macrophage content in anti-miR33 treated diabetic mice was associated with a blunting of hyperglycemia-induced monocytosis and reduced monocyte recruitment to the plaque, which was traced to an inhibition of the proliferation of bone marrow monocyte precursors associated with the upregulation of their Abca1.
  
  
  CONCLUSIONS
  miR33 inhibition overcomes deleterious effects of diabetes mellitus in atherosclerosis regression in mice, which suggests a therapeutic strategy in diabetic patients, who remain at elevated cardiovascular disease risk, despite plasma cholesterol lowering.
authors.affiliation: From the Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, Department of Medicine (E.D., T.J.B., K.C., S.P., K.J.M., E.A.F.) and Department of Microbiology (N.M.G.), New York University School of Medicine, NY; Regulus Therapeutics, San Diego, CA (C.C.E.); Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.J.M.); and Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.).
authors.forename: Emilie
authors.initials: E
authors.lastname: Distel
authors.affiliation: From the Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, Department of Medicine (E.D., T.J.B., K.C., S.P., K.J.M., E.A.F.) and Department of Microbiology (N.M.G.), New York University School of Medicine, NY; Regulus Therapeutics, San Diego, CA (C.C.E.); Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.J.M.); and Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.).
authors.forename: Tessa J
authors.initials: TJ
authors.lastname: Barrett
authors.affiliation: From the Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, Department of Medicine (E.D., T.J.B., K.C., S.P., K.J.M., E.A.F.) and Department of Microbiology (N.M.G.), New York University School of Medicine, NY; Regulus Therapeutics, San Diego, CA (C.C.E.); Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.J.M.); and Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.).
authors.forename: Kellie
authors.initials: K
authors.lastname: Chung
authors.affiliation: From the Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, Department of Medicine (E.D., T.J.B., K.C., S.P., K.J.M., E.A.F.) and Department of Microbiology (N.M.G.), New York University School of Medicine, NY; Regulus Therapeutics, San Diego, CA (C.C.E.); Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.J.M.); and Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.).
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Girgis
authors.affiliation: From the Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, Department of Medicine (E.D., T.J.B., K.C., S.P., K.J.M., E.A.F.) and Department of Microbiology (N.M.G.), New York University School of Medicine, NY; Regulus Therapeutics, San Diego, CA (C.C.E.); Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.J.M.); and Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.).
authors.forename: Saj
authors.initials: S
authors.lastname: Parathath
authors.affiliation: From the Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, Department of Medicine (E.D., T.J.B., K.C., S.P., K.J.M., E.A.F.) and Department of Microbiology (N.M.G.), New York University School of Medicine, NY; Regulus Therapeutics, San Diego, CA (C.C.E.); Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.J.M.); and Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.).
authors.forename: Christine C
authors.initials: CC
authors.lastname: Essau
authors.affiliation: From the Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, Department of Medicine (E.D., T.J.B., K.C., S.P., K.J.M., E.A.F.) and Department of Microbiology (N.M.G.), New York University School of Medicine, NY; Regulus Therapeutics, San Diego, CA (C.C.E.); Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.J.M.); and Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.).
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: From the Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, Department of Medicine (E.D., T.J.B., K.C., S.P., K.J.M., E.A.F.) and Department of Microbiology (N.M.G.), New York University School of Medicine, NY; Regulus Therapeutics, San Diego, CA (C.C.E.); Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.J.M.); and Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.).
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.affiliation: From the Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, Department of Medicine (E.D., T.J.B., K.C., S.P., K.J.M., E.A.F.) and Department of Microbiology (N.M.G.), New York University School of Medicine, NY; Regulus Therapeutics, San Diego, CA (C.C.E.); Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.J.M.); and Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.). edward.fisher@nyumc.org kathryn.moore@nyumc.org.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000235:genetics / Q000628:therapy*; D003925:Diabetic Angiopathies / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D066273:Diet, Western; D018450:Disease Progression; D020868:Gene Silencing; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D018836:Inflammation Mediators; D008055:Lipids; D008074:Lipoproteins; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D011973:Receptors, LDL; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C550417:Mirn33 microRNA, mouse; C106092:microsomal triglyceride transfer protein
keywords: atherosclerosis; diabetes mellitus; high-density lipoprotein; microRNA; regression