Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: role of Rac1/2-sensitive Nox-dependent pathways

Author(s)

Bruder-Nascimento, Thiago ^{[1, 2]} ; Callera, Glaucia E. ^[2] ; Montezano, Augusto C. ^[3] ; He, Ying ^[2] ; Antunes, Tayze T. ^[2] ; Cat, Aurelie Nguyen Dinh ^[3] ; Tostes, Rita C. ^[1] ; Touyz, Rhian M. ^{[3, 2]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Sao Paulo - Brazil

^[2] Univ Ottawa, Kidney Res Ctr, Ottawa Hosp Res Inst, Ottawa, ON - Canada

^[3] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark - Scotland

• Document type: Journal article
• Source: Clinical Science; v. 128, n. 7, p. 411-423, APR 2015.
• Web of Science Citations: 20

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 I kappa B-alpha and increased NF-kappa B p50 expression, increased NF-kappa B 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. (AU)

• FAPESP's process: 11/01785-6 - Contribution of oxidative stress and NOXes to diabetes-associated vascular injury
• Grantee: Thiago Bruder Do Nascimento
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/52214-6 - Contribution of oxidative stress and NOXes to diabetes-associated vascular and renal injury
• Grantee: Rita de Cassia Aleixo Tostes Passaglia
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/22035-5 - Contribution of oxidative stress and NADPH oxidase (NOXes) diabetes-associated vascular injury: study in knockout mice
• Grantee: Thiago Bruder Do Nascimento
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate