Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling

Silva, M. A.B., Bruder-Nascimento, T., Cau, S. B.A., Lopes, R. A.M. , Mestriner, F. L.A.C., Fais, R. S., Touyz, R. M. and Tostes, R. C. (2015) Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling. Frontiers in Physiology, 6, 269. (doi:10.3389/fphys.2015.00269)

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Abstract

Type 2 diabetes (DM2) increases the risk of cardiovascular disease. Aldosterone, which has pro-oxidative and pro-inflammatory effects in the cardiovascular system, is positively regulated in DM2. We assessed whether blockade of mineralocorticoid receptors (MR) with spironolactone decreases reactive oxygen species (ROS)-associated vascular dysfunction and improves vascular nitric oxide (NO) signaling in diabetes. Leptin receptor knockout [LepRdb/LepRdb (db/db)] mice, a model of DM2, and their counterpart controls [LepRdb/LepR+, (db/+) mice] received spironolactone (50 mg/kg body weight/day) or vehicle (ethanol 1%) via oral per gavage for 6 weeks. Spironolactone treatment abolished endothelial dysfunction and increased endothelial nitric oxide synthase (eNOS) phosphorylation (Ser1177) in arteries from db/db mice, determined by acetylcholine-induced relaxation and Western Blot analysis, respectively. MR antagonist therapy also abrogated augmented ROS-generation in aorta from diabetic mice, determined by lucigenin luminescence assay. Spironolactone treatment increased superoxide dismutase-1 and catalase expression, improved sodium nitroprusside and BAY 41-2272-induced relaxation, and increased soluble guanylyl cyclase (sGC) β subunit expression in arteries from db/db mice. Our results demonstrate that spironolactone decreases diabetes-associated vascular oxidative stress and prevents vascular dysfunction through processes involving increased expression of antioxidant enzymes and sGC. These findings further elucidate redox-sensitive mechanisms whereby spironolactone protects against vascular injury in diabetes.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lopes, Dr Rheure and Touyz, Professor Rhian
Authors: Silva, M. A.B., Bruder-Nascimento, T., Cau, S. B.A., Lopes, R. A.M., Mestriner, F. L.A.C., Fais, R. S., Touyz, R. M., and Tostes, R. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Frontiers in Physiology
Publisher:Frontiers Research Foundation
ISSN:1664-042X
ISSN (Online):1664-042X
Copyright Holders:Copyright © 2015 Silva, Bruder-Nascimento, Cau, Lopes, Mestriner, Fais, Touyz and Tostes
First Published:First published in Frontiers in Physiology 6:269
Publisher Policy:Reproduced under a Creative Commons License

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