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)
Type
Research Program Projects (P01)
Project #
2P01HL069999-11A1
Application #
8701530
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Type
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Pollock, David M (2014) 2013 Dahl Lecture: American Heart Association council for high blood pressure research clarifying the physiology of endothelin. Hypertension 63:e110-7
Su, Shaoyong; Zhu, Haidong; Xu, Xiaojing et al. (2014) DNA methylation of the LY86 gene is associated with obesity, insulin resistance, and inflammation. Twin Res Hum Genet 17:183-91
Riese, Harriëtte; Muñoz, Loretto M; Hartman, Catharina A et al. (2014) Identifying genetic variants for heart rate variability in the acetylcholine pathway. PLoS One 9:e112476
Hyndman, Kelly A; Ho, Dao H; Sega, Martiana F et al. (2014) Histone deacetylase 1 reduces NO production in endothelial cells via lysine deacetylation of NO synthase 3. Am J Physiol Heart Circ Physiol 307:H803-9
Su, Shaoyong; Wang, Xiaoling; Kapuku, Gaston K et al. (2014) Adverse childhood experiences are associated with detrimental hemodynamics and elevated circulating endothelin-1 in adolescents and young adults. Hypertension 64:201-7
Jin, Chunhua; Jeon, Yejoo; Kleven, Daniel T et al. (2014) Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome. J Pharmacol Exp Ther 351:467-73
Kittikulsuth, W; Sullivan, J C; Pollock, D M (2013) ET-1 actions in the kidney: evidence for sex differences. Br J Pharmacol 168:318-26
Loria, Analia S; Brands, Michael W; Pollock, David M et al. (2013) Early life stress sensitizes the renal and systemic sympathetic system in rats. Am J Physiol Renal Physiol 305:F390-5
Spradley, F T; Kang, K-T; Pollock, J S (2013) Short-term hypercaloric diet induces blunted aortic vasoconstriction and enhanced vasorelaxation via increased nitric oxide synthase 3 activity and expression in Dahl salt-sensitive rats. Acta Physiol (Oxf) 207:358-68
Kittikulsuth, Wararat; Looney, Stephen W; Pollock, David M (2013) Endothelin ET(B) receptors contribute to sex differences in blood pressure elevation in angiotensin II hypertensive rats on a high-salt diet. Clin Exp Pharmacol Physiol 40:362-70

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