P759Novel therapeutic approach to target endothelial dysfunction in type 2 diabetes

Abstract

Purpose: To determine whether activators of NFE2-related factor 2 (Nrf2) can be used in addition with inhibitors of advanced glycation end products formation to attenuate oxidative stress and improve endothelial dysfunction in type 2 diabetes. In this study we investigate pyridoxamine (PM) and/or sulforaphane (SFN) as therapeutic interventions in endothelial dysfunction associated with type 2 diabetes in both aorta and mesenteric arteries. Methods: Goto-kakizaki (GK) rats, an animal model of non-obese type 2 diabetes and age-matched control Wistar rats were treated with or without PM (100 mg/kg/day) and /or SFN (1 mg/kg/day) during 8 weeks. At the end of the treatment, nitric oxide (NO)-dependent and independent vasorelaxation in isolated aorta and mesenteric arteries were evaluated. Metabolic profile, NO bioavailability, glycation, inflammation and vascular oxidative stress were also assessed. Results: Diabetic GK rats presented significantly lower levels of Nrf2 (p<0.001), antioxidant enzymes and concomitantly exhibits higher levels of oxidative stress, glycation, inflammation and endothelial dysfunction (associated with decrease NO bioavailability). PM and SFN were both capable of significantly improve endothelial dysfunction (by 20 and 25 %, respectively), inflammation and oxidative stress in aorta and mesenteric arteries. PM and SFN as monotherapy significantly decreased vascular oxidative damage (accumulation of anion superoxide and 3-nitrotyrosine in arteries) and inflammation (levels of monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1 in arteries). SFN up-regulated Nrf2 expression and transcription activity that was reflected by increased Nrf2 nuclear accumulation and phosphorylation as well as the protein expression of Nrf2 downstream antioxidants. Furthermore, both therapeutics in association proved more effective and were capable of reducing to a greater extent oxidative stress and inflammation improving endothelial function and metabolic profile in GK diabetic rats. Conclusions: We provide experimental evidence indicating that activators of Nrf2 can be used therapeutically in association with inhibitors of AGEs formation to improve metabolic profile and relieve endothelial dysfunction in type 2 diabetes.