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

Bruder‑Nascimento, T., Callera, G. E., Montezano, A. C., He, Y., Antunes, T. T., Nguyen Dinh Cat, A., Tostes, R. C. and Touyz, R. M. (2014) Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: role of Rac1/2-sensitive nox-dependent pathways. Clinical Science, 128(7), pp. 411-423. (doi:10.1042/CS20140456)

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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. Leprdb/Leprdb (db/db) mice, a model of Type 2 diabetes and control Leprdb/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 p47phox 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nguyen Dinh Cat, Dr Aurelie and Montezano, Dr Augusto and Touyz, Professor Rhian
Authors: Bruder‑Nascimento, T., Callera, G. E., Montezano, A. C., He, Y., Antunes, T. T., Nguyen Dinh Cat, A., Tostes, R. C., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Clinical Science
Publisher:Biochemical Society
ISSN:0143-5221
ISSN (Online):1470-8736
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