Epidemiological studies in humans link adversity early in life, such as low parental socioeconomic status (SES), to cardiovascular disease (CVD) in adulthood by. hastening the trajectory of disease progression. Increased adiposity in youth also predisposes adults to CVD and? hypertension. Our overall goals are to elucidate the mechanism(s) of ELS and increased adiposity, working in concert, to promote hypertension as well as to define the ELS-induced mechanisms leading to blunted endothelial function in adults. We will also incorporate human mechanistic studies by evaluating endothelial-dependent function in adults from low and high childhood SES. High fat diet consumption increases adiposity similarly in control and animals ?exposed to ELS. Yet, we found that increased adiposity, specifically in ELS animals, elevates blood pressure and increases angiotensin II (Angll). Chronic Angll infusion in animals exposed to ELS develop increased blood pressure more rapidly and to a higher degree as well as exaggerated renal vascular damage and increased T cell infiltration in the renal cortex compared to Angll infusion in control animals. T cells and isolated renal vessels from animals only exposed to ELS reveal induction of pro-inflammatory genes. We propose to test the hypothesis that ELS and increased adiposity, in concert, mediate Angll-depcmdent T cell-specific TNF activation leading to renal dysfunction and elevated blood pressure in adults. Ex vivo studies in aortae from adult rodents exposed to ELS show endothelial dysfunction and loss of NO bioavailability. Moreover, our studies show that ELS induces histone deacetylase (HDAC) expression in aortic tissue and inhibition of HDAC activity abolished the ELS-induced endothelial dysfunction. We propose to test the hypothesis that ELS induces endothelial dysfunction via increased HDAC-mediated reduced NOS activation and decreased NO bioavailability. Numerous studies establish that low childhood SES associates with CVD risk factors,. although little is known about the mechanism(s). Utilizing data from the PPG cohort, our group reported that low parental SES was positively correlated to increased mean arterial blood pressure and high blood pressure variability with increasing age in adults. We propose translating our research in animal models to humans by testing the hypothesis that exposure to low parental SES predisposes adults to endothelial dysfunction via loss of NO bioavailability and increased HDAC activity.

Public Health Relevance

to Public Health: Essential hypertension is the number 1 reason for a physician visit, with 1 in 3 people suffering from the disorder. Stress and obesity are known determinants of hypertension, however specific effective treatment strategies and preventive interventions are lacking. This knowledge will enable us to develop new and effective prevention and treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL069999-15
Application #
9526525
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Stoney, Catherine
Project Start
Project End
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Augusta University
Department
Type
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Gohar, Eman Y; Giachini, Fernanda R; Pollock, David M et al. (2016) Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases. Life Sci 159:20-29

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