There is evidence that endotheliopathy is intrinsic to obesity/insulin resistance and, in turn, type 2 diabetes. Alterations in vasomotor function, specifically an imbalance between vasodilation and vasoconstriction, occurring in the obese/insulin resistant prediabetic stage is thought to contribute to the accelerated rates of atherosclerotic vascular disease in type 2 diabetes. Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. In addition to its effects on vascular tone, ET-1 has been linked to the initiation and development of atherosclerosis. Importantly, oxidative stress is associated with obesity/insulin resistance, impaired endothelium-dependent vasodilation and increased ET-1 production and activity.
The specific aims of the present proposal will be to determine: 1) whether the vasoconstrictor activity of endogenous ET-1 is increased in obese/insulin resistant adult humans; 2) if oral vitamin C supplementation reduces endogenous ET-1 vasoconstrictor activity in obese/insulin resistant adults as much or more than regular aerobic exercise; and 3) if oral vitamin C supplementation improves endotheliumdependent vasodilation in obese/insulin resistant adult humans as much or more than regular aerobic exercise; and to determine whether improvements in endothelial vasodilation is due, at least in part, to reduced ET-1 vasoconstrictor activity. To address these aims, 252 middle-aged and older obese/insulin resistant and lean/insulin sensitive adult humans will be studied. Endogenous ET-1 vasoconstrictor activity will be assessed by changes in forearm blood flow (plethysmography) in response to intra-arterial infusion of selective and nonselective ET-1 receptor antagonists as well as exogenous ET-1. In addition, the vasodilator response to both acetylcholine and sodium nitroprusside will be determined in the absence and presence of ET-1 receptor blockade. Endogenous ET-1 vasoconstrictor activity will also be assessed before and after a 12-week intervention of either oral vitamin C supplementation (500 mg/d) or aerobic exercise training in obese/insulin resistant adults. The results of the proposed study should provide clinically important information regarding the activity of the ET-1 system with obesity/insulin resistance; and the efficacy of vitamin C supplementation in reducing ET-l-mediated vasoconstriction and, in turn, improving endothelial vasomotor regulation in obese/insulin resistant adults.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076434-04
Application #
7230492
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Program Officer
Rabadan-Diehl, Cristina
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$285,820
Indirect Cost
Name
University of Colorado at Boulder
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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Diehl, Kyle J; Weil, Brian R; Westby, Christian M et al. (2012) Effects of endothelin-1 on endothelial progenitor cell function. Clin Chem Lab Med 50:1121-4
Weil, Brian R; Westby, Christian M; Greiner, Jared J et al. (2012) Elevated endothelin-1 vasoconstrictor tone in prehypertensive adults. Can J Cardiol 28:347-53

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