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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CCVS (01))
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Rabadan-Diehl, Cristina
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Dow, Caitlin A; Templeton, Danielle L; Lincenberg, Grace M et al. (2016) Elevations in C-reactive protein and endothelin-1 system activity in humans. Life Sci 159:66-70
Diehl, K J; Weil, B R; Greiner, J J et al. (2015) Impaired endogenous fibrinolytic capacity in prehypertensive men. J Hum Hypertens 29:468-72
Dow, Caitlin A; Stauffer, Brian L; Greiner, Jared J et al. (2014) Influence of dietary saturated fat intake on endothelial fibrinolytic capacity in adults. Am J Cardiol 114:783-8
Fasing, Kevin A; Nissan, Benjamin J; Greiner, Jared J et al. (2014) Influence of elevated levels of C-reactive protein on circulating endothelial progenitor cell function. Clin Transl Sci 7:137-40
Diehl, Kyle J; Stauffer, Brian L; Greiner, Jared J et al. (2014) ENDOTHELIN-1 SYTEM ACTIVITY IN ADULTS WITH BORDERLINE HIGH LDL-CHOLESTEROL. Artery Res 8:115-118
Rocha, Natalia G; Templeton, Danielle L; Greiner, Jared J et al. (2014) Metabolic syndrome and endothelin-1 mediated vasoconstrictor tone in overweight/obese adults. Metabolism 63:951-6
Diehl, Kyle J; Templeton, Danielle L; Ma, Julie et al. (2013) Impaired fasting blood glucose is associated with increased endothelin-1 vasoconstrictor tone. Atherosclerosis 229:130-3
Weil, Brian R; Greiner, Jared J; Stauffer, Brian L et al. (2013) Self-reported habitual short sleep duration is associated with endothelial fibrinolytic dysfunction in men: a preliminary report. Sleep 36:183-8
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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