title: Insulin decreases atherosclerotic plaque burden and increases plaque stability via nitric oxide synthase in apolipoprotein E-null mice.
abstract: It has been argued whether insulin accelerates or prevents atherosclerosis. Although results from in vitro studies have been conflicting, recent in vivo mice studies demonstrated antiatherogenic effects of insulin. Insulin is a known activator of endothelial nitric oxide synthase (NOS), leading to increased production of NO, which has potent antiatherogenic effects. We aimed to examine the role of NOS in the protective effects of insulin against atherosclerosis. Male apolipoprotein E-null mice (8 wk old) fed a high-cholesterol diet (1.25% cholesterol) were assigned to the following 12-wk treatments: control, insulin (0.05 U/day via subcutaneous pellet), N(ω)-nitro-l-arginine methyl ester hydrochloride (l-NAME, via drinking water at 100 mg/l), and insulin plus l-NAME. Insulin reduced atherosclerotic plaque burden in the descending aorta by 42% compared with control (plaque area/aorta lumen area: control, 16.5 ± 1.9%; insulin, 9.6 ± 1.3%, P < 0.05). Although insulin did not decrease plaque burden in the aortic sinus, macrophage accumulation in the plaque was decreased by insulin. Furthermore, insulin increased smooth muscle actin and collagen content and decreased plaque necrosis, consistent with increased plaque stability. In addition, insulin treatment increased plasma NO levels, decreased inducible NOS staining, and tended to increase phosphorylated vasodilator-stimulated phosphoprotein staining in the plaques of the aortic sinus. All these effects of insulin were abolished by coadministration of l-NAME, whereas l-NAME alone showed no effect. Insulin also tended to increase phosphorylated endothelial NOS and total neuronal NOS staining, effects not modified by l-NAME. In conclusion, we demonstrate that insulin treatment decreases atherosclerotic plaque burden and increases plaque stability through NOS-dependent mechanisms.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa, Tokyo, Japan;
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Simon
authors.initials: S
authors.lastname: Chiang
authors.affiliation: Department of Laboratory Medicine and Pathobiology, Ted Rogers Centre for Heart Research TBEP/ University of Toronto, Ontario, Canada; and.
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Bendeck
authors.affiliation: Department of Physiology and Medicine, Institute of Medical Science, Banting and Best Diabetes Centre, Toronto, Ontario, Canada.
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
mesh_terms: D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009336:Necrosis; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000187:drug effects / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology; D012850:Sinus of Valsalva / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000199:Actins; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D010750:Phosphoproteins; C544013:alpha-smooth muscle actin, mouse; D003094:Collagen; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; D019331:NG-Nitroarginine Methyl Ester
keywords: apolipoprotein E-null mice; atherosclerosis; insulin; nitric oxide synthase