Abstract P034: Endothelin-1 Overexpression Exaggerates Diabetes-induced Endothelial Dysfunction by Altering Oxidative Stress Balance

Abstract

Objective: Increased endothelin (ET)-1 expression has been shown to cause endothelial dysfunction.Plasma ET-1 is increased in patients with diabetes.Since endothelial dysfunction often precedes vascular complications in diabetes, we sought to determine whether ET-1 contributes to diabetes-induced endothelial dysfunction. We hypothesized that overexpression of ET-1 in the endotheliumwill exaggerate diabetes-induced endothelial dysfunction. Method: Diabetes was induced by streptozotocin treatment (STZ, 55 mg/kg/day, ip) for 5 days in 6weekold male wild-type (WT) mice and in mice overexpressinghuman ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Blood glucose,plasma ET-1 levels, mesenteric artery (MA) reactivity, mitochondrial superoxide production in aorta and endothelial nitric oxide synthase (Nos3), superoxide dismutase 1 (Sod1) and 2 (Sod2) mRNA expression in MA were determined. Results: STZ-induced diabetes was confirmed by increased glycemia in WT(27.6±1.5 vs 10.7±1.1 μM, P<0.001)and eET-1 (23.2±1.0 vs 8.4±0.3 μM, P<0.001).Plasma ET-1 was increased in vehicle- (15.9±4.6 vs 0.6±0.04pg/mL, P<0.05) and STZ-treatedeET-1 (4.9±0.6 vs 0.8±0.1 pg/mL, P<0.05) compared to respective WT controls.Diabetes caused a reduction in vasodilatory responses to acetylcholine in WT (60.9±6.4% vs 83.9±3.4%,P<0.05), which was exaggerated in eET-1(48.6±5.1% vs 81.5±5.2% P<0.05). Mitochondrial superoxide production was increased by diabetes in WT (38.0±4.3 vs 21.6±2.3 RFU/μm2,P<0.05)and further augmented in eET-1 (49.8±1.7 RFU/μm2P<0.05).Nos3 expression was increased in vehicle-treatedeET-1 compared to WT(1.43±0.19 vs 1.00±0.10, P<0.05).Diabetes reduced Nos3 expression in eET-1 (0.75±0.08, P<0.05) but not in WT(1.08±0.09).Diabetes caused an increase in Sod1(1.52±0.17 vs 1.00±0.03, P<0.05) and Sod2 (1.32±0.17 vs 1.00±0.02, P<0.05) expression in WT (P<0.05) but not in eET-1. Conclusions: Increased levels of ET-1 exaggerate diabetes-induced endothelial dysfunction. This may be caused by a decrease in Nos3 expression, an increase in mitochondrial oxidative stress and a decrease in antioxidant capacity.