Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and...

Area of Science:

• Cardiovascular Research
• Endocrinology
• Pharmacology

Background:

• Type 2 diabetes (DM2) significantly elevates cardiovascular disease risk.
• Aldosterone, implicated in cardiovascular oxidative stress and inflammation, is upregulated in DM2.
• Mineralocorticoid receptor (MR) blockade is a potential therapeutic strategy for diabetic vascular complications.

Purpose of the Study:

• To investigate if spironolactone, an MR antagonist, mitigates reactive oxygen species (ROS)-induced vascular dysfunction in a mouse model of DM2.
• To determine if spironolactone improves vascular nitric oxide (NO) signaling pathways in diabetic conditions.

Main Methods:

• Leptin receptor knockout [LepR(db)/LepR(db) (db/db)] mice, a model for DM2, and control [LepR(db)/LepR(+), (db/+) mice] were treated with spironolactone (50 mg/kg/day) or vehicle for 6 weeks.
• Vascular function was assessed via acetylcholine-induced relaxation assays.
• Endothelial nitric oxide synthase (eNOS) phosphorylation, ROS generation (lucigenin luminescence), and expression of antioxidant enzymes (superoxide dismutase-1, catalase) and soluble guanylyl cyclase (sGC) subunits were analyzed.

Main Results:

• Spironolactone treatment normalized endothelial dysfunction in db/db mice.
• The treatment increased eNOS phosphorylation (Ser1177) and abrogated elevated ROS generation in diabetic arteries.
• Spironolactone enhanced the expression of antioxidant enzymes and increased sGC β subunit expression, improving relaxation responses to NO donors.

Conclusions:

• Spironolactone effectively decreases diabetes-associated vascular oxidative stress.
• The drug prevents vascular dysfunction in DM2 by enhancing antioxidant capacity and improving NO-sGC signaling.
• These findings highlight redox-sensitive mechanisms underlying spironolactone's protective effects against vascular injury in diabetes.