LBPS 01-03 ENDOTHELIN-1 OVEREXPRESSION EXAGGERATES DIABETES-INDUCED ENDOTHELIAL DYSFUNCTION BY ALTERING OXIDATIVE STRESS BALANCE

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Abstract

Objective:

Increased endothelin (ET)-1 expression has been shown to cause endothelial dysfunction and oxidative stress. Plasma ET-1 is increased in patients with diabetes mellitus. 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 endothelium will exaggerate diabetes-induced endothelial dysfunction.

Design and Method:

Diabetes was induced by streptozotocin treatment (STZ, 55 mg/kg/day, ip) for 5 days in 6 week-old male wild-type (WT) mice and in mice overexpressing human ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Endothelial function and vascular remodeling using pressurized myography, reactive oxygen species (ROS) production by dihydroethidium staining and mRNA expression by reverse transcription-quantitative PCR were assessed in mesenteric arteries (MA).

Results:

MA endothelium-dependent vasodilatory responses to acetylcholine were reduced 24% by diabetes in WT, and further decreased by 12% in eET-1. Diabetes decreased MA media/lumen in WT and eET-1 whereas ET-1 overexpression increased MA media/lumen to a similar extent in diabetic and non-diabetic WT mice. Vascular ROS production in MA was increased 2-fold by diabetes in WT and further augmented 1.7-fold in eET-1. Diabetes reduced endothelial nitric oxide synthase (eNOS, Nos3) mRNA expression in eET-1 by 31% but not in WT. Induction of diabetes caused a 52% increase in superoxide dismutase 1 (Sod1) and a 32% increase in Sod2 (32%) mRNA expression in WT but not in eET-1.

Conclusions:

Increased expression of ET-1 exaggerates diabetes-induced endothelial dysfunction. This may be caused by a decrease in eNOS expression, an increase in vascular oxidative stress and a decrease in antioxidant capacity.

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