Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling.
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)/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 (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) 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.
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo Ribeirão Preto, Brazil.
Marcondes A B
MA
Silva
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo Ribeirão Preto, Brazil.
Thiago
T
Bruder-Nascimento
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo Ribeirão Preto, Brazil.
Stefany B A
SB
Cau
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo Ribeirão Preto, Brazil.
Rheure A M
RA
Lopes
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo Ribeirão Preto, Brazil.
Fabiola L A C
FL
Mestriner
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo Ribeirão Preto, Brazil.
Rafael S
RS
Fais
BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical sciences, University of Glasgow Glasgow, UK.
Rhian M
RM
Touyz
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo Ribeirão Preto, Brazil.
Rita C
RC
Tostes
aldosterone; mineralocorticoid receptor; oxidative stress; type 2 diabetes; vascular