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.
Highlights
In the past two decades, the number of people diagnosed with diabetes worldwide has dramatically increased (Zimmet et al, 2001)
12–14 weeks-old, [B6.BKS(D)-Lepr/J] mice, an experimental model of DM2, and 14 agematched heterozygous nondiabetic mice [(db/+), from The Jackson Laboratory, Maine, USA were used in the study. db/+ and db/db mice were divided into four groups (7 mice per group): db/+ spironolactone and db/db spironolactone, which were treated for 6 weeks with the mineralocorticoid receptors (MR) antagonist spironolactone (50 mg/kg body weight/day), and db/+ vehicle and db/db vehicle, which were treated with ethanol 1% via oral per gavage (0.1 ml per 10 g of the total body weight)
Effects of Spironolactone Treatment on Systolic Blood Pressure, Glucose Levels, and Biochemistry Parameters Db/db mice exhibited higher plasma glucose levels compared to db/+ mice (p < 0.05)
Summary
In the past two decades, the number of people diagnosed with diabetes worldwide has dramatically increased (Zimmet et al, 2001). Type 2 diabetes mellitus (DM2), characterized by insulin resistance and/or abnormal insulin secretion, either of which may predominate, affects 7.6 million people in Brazil, 26 million in the United States and 347 million worldwide (Zimmet et al, 2001; Manrique et al, 2014). We have recently shown that db/db mice, a DM2 experimental model, present increased expression/activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) isoforms leading to inflammation and, to vascular dysfunction (Bruder-Nascimento et al, 2015). On the other hand, reduced antioxidant enzymes expression/activity has been reported in DM2 (Bruder-Nascimento et al, 2014)
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