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)

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: Alves Moreira 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 > School of Cardiovascular & Metabolic Health
• 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