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

Author(s)

Silva, Marcondes A. B. ^[1] ; Bruder-Nascimento, Thiago ^[1] ; Cau, Stefany B. A. ^[1] ; Lopes, Rheure A. M. ^[1] ; Mestriner, Fabiola L. A. C. ^[1] ; Fais, Rafael S. ^[1] ; Touyz, Rhian M. ^[2] ; Tostes, Rita C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark - Scotland

• Document type: Journal article
• Source: FRONTIERS IN PHYSIOLOGY; v. 6, OCT 5 2015.
• Web of Science Citations: 10

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 {[}LepR(db)/LepR(db) (db/db)] mice, a model of DM2, and their counterpart controls {[}LepR(db)/Lep(R+)(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 (Ser(1177)) 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) beta, 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. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• 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