The metabolic syndrome, defined by a clustering of interrelated risk factors of metabolic and vascular origin, is a major public-health issue affecting ~47 million US residents. The prevalence of the metabolic syndrome is especially high in middle-aged and older adults occurring in ~44% of men and women over 50 years of age. Aging and the metabolic syndrome are associated with increased risk for cardiovascular disease and death. Atherosclerosis is the major contributor to cardiovascular morbidity and mortality. Vascular endothelial dysfunction, a critical early event in the pathogenesis of atherosclerosis, is common in patients with the metabolic syndrome, as well as in older adults. However, the mechanisms responsible for this impairment are poorly understood. The proposed research will determine if blockade of the mineralocorticoid receptors improves vascular endothelium-dependent dilation, a clinically relevant marker of endothelial function, in middle-aged and older adults with the metabolic syndrome. We will also investigate the role of oxidative stress and inflammation in mediating these beneficial effects. Our working hypothesis is that mineralocorticoid receptor blockade will lead to improved endothelium-dependent dilation. This improvement will be associated with greater reductions in biomarkers of oxidative stress and inflammation. Individuals with elevated baseline levels of these biomarkers will experience the greatest improvement in vascular endothelial function after the blockade. To test our working hypothesis we will conduct a balanced randomized, double-blind, cross-over study. Measurements will be performed twice, once after mineralocorticoid receptor blockade (Eplerenone) and once after placebo (i.e., control condition). Endothelium-dependent dilation (brachial artery flow mediated dilation) and endothelium-independent dilation (brachial artery dilation in response to sublingual nitroglycerin) will be determined non-invasively using high resolution duplex ultrasonography. Insight to the molecular mechanisms mediating the impairment in vascular endothelial function and improvement following mineralocorticoid receptor blockade will be obtained using a novel translational research technique of collecting human endothelial cells and determining protein expression of pro- and anti-atherogenic factors via quantitative immunofluorescence. Systemic biomarkers of oxidative stress and inflammation will also be determined in blood. The expected results should significantly extend our current understanding of the integrative (whole-body to molecular) physiological mechanisms underlying vascular endothelial dysfunction in aging and the metabolic syndrome. These findings may have important implications in the development of strategies for preventing and treating atherosclerosis associated with aging and the metabolic syndrome.

Public Health Relevance

The metabolic syndrome, defined by the coexistence of multiple cardiovascular risk factors, is a major public- health issue. The occurrence of the metabolic syndrome is especially high in middle-aged and older adults. The proposed study will investigate in middle-aged and older adults with the metabolic syndrome, whether mineralocorticoid receptors contribute to vascular endothelial dysfunction, a key early event in the development of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
7R03AG032067-03
Application #
8137543
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Zieman, Susan
Project Start
2008-09-15
Project End
2012-08-31
Budget Start
2010-09-30
Budget End
2012-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$23,755
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Allied Health Profes
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith et al. (2016) Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults. Exp Gerontol 73:86-94
DuPont, Jennifer J; McCurley, Amy; Davel, Ana P et al. (2016) Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging. JCI Insight 1:e88942
Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith et al. (2015) Effect of Selective Mineralocorticoid Receptor Blockade on Flow-Mediated Dilation and Insulin Resistance in Older Adults with Metabolic Syndrome. Metab Syndr Relat Disord 13:356-61
Yoo, Jeung-Ki; Hwang, Moon-Hyon; Luttrell, Meredith J et al. (2015) Higher levels of adiponectin in vascular endothelial cells are associated with greater brachial artery flow-mediated dilation in older adults. Exp Gerontol 63:1-7
Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith et al. (2013) Mineralocorticoid receptors modulate vascular endothelial function in human obesity. Clin Sci (Lond) 125:513-20
Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith et al. (2013) Role of mineralocorticoid receptors in arterial stiffness in human aging. Exp Gerontol 48:701-4
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