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

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Clinical Science; v. 128, n. 7, p. 411-423, APR 2015.
• Citações Web of Science: 21

Resumo

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)

• Processo FAPESP: 10/52214-6 - Contribuição do estresse oxidativo e enzimas NADPH oxidases (NOXes) para as lesões vasculares e renais associadas ao diabetes
• Beneficiário: Rita de Cassia Aleixo Tostes Passaglia
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/22035-5 - Contribuição do estresse oxidativo e enzimas NADPH oxidases (NOXes) para as lesões vasculares associadas ao diabetes: estudo em camundongos nocautes
• Beneficiário: Thiago Bruder Do Nascimento
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 11/01785-6 - Contribuição do estresse oxidativo e enzimas NADPH oxidases (NOXes) para as lesões vasculares associadas ao diabetes
• Beneficiário: Thiago Bruder Do Nascimento
• Linha de fomento: Bolsas no Brasil - Doutorado