title: Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: role of Rac1/2-sensitive Nox-dependent pathways.
abstract: Oxidative stress [increased bioavailability of reactive oxygen species (ROS)] plays a role in the endothelial dysfunction and vascular inflammation, which underlie vascular damage in diabetes. Statins are cholesterol-lowering drugs that are vasoprotective in diabetes through unknown mechanisms. We tested the hypothesis that atorvastatin decreases NADPH oxidase (Nox)-derived ROS generation and associated vascular injury in diabetes. Lepr(db)/Lepr(db) (db/db) mice, a model of Type 2 diabetes and control Lepr(db)/Lepr(+) (db/+) mice were administered atorvastatin (10 mg/kg per day, 2 weeks). Atorvastatin improved glucose tolerance in db/db mice. Systemic and vascular oxidative stress in db/db mice, characterized by increased plasma TBARS (thiobarbituric acid-reactive substances) levels and exaggerated vascular Nox-derived ROS generation respectively, were inhibited by atorvastatin. Cytosol-to-membrane translocation of the Nox regulatory subunit p47(phox) and the small GTPase Rac1/2 was increased in vessels from db/db mice compared with db/+ mice, an effect blunted by atorvastatin. The increase in vascular Nox1/2/4 expression and increased phosphorylation of redox-sensitive mitogen-activated protein kinases (MAPKs) was abrogated by atorvastatin in db/db mice. Pro-inflammatory signalling (decreased IκB-α and increased NF-κB p50 expression, increased NF-κB p65 phosphorylation) and associated vascular inflammation [vascular cell adhesion molecule-1 (VCAM-1) expression and vascular monocyte adhesion], which were increased in aortas of db/db mice, were blunted by atorvastatin. Impaired acetylcholine (Ach)- and insulin (INS)-induced vasorelaxation in db/db mice was normalized by atorvastatin. Our results demonstrate that, in diabetic mice, atorvastatin decreases vascular oxidative stress and inflammation and ameliorates vascular injury through processes involving decreased activation of Rac1/2 and Nox. These findings elucidate redox-sensitive and Rac1/2-dependent mechanisms whereby statins protect against vascular injury in diabetes.
authors.affiliation: *Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Thiago
authors.initials: T
authors.lastname: Bruder-Nascimento
authors.affiliation: †Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.affiliation: ‡Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.affiliation: †Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: †Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Tayze T
authors.initials: TT
authors.lastname: Antunes
authors.affiliation: ‡Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.affiliation: *Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.affiliation: †Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000069059:Atorvastatin; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008297:Male; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000109:Acetylcholine; D000069059:Atorvastatin; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D020928:Mitogen-Activated Protein Kinases; D019255:NADPH Oxidases; D011758:Pyrroles; D017382:Reactive Oxygen Species; D054411:Receptors, Leptin; D017392:Thiobarbituric Acid Reactive Substances; D014665:Vasodilator Agents; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C060505:neutrophil cytosolic factor 1