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
De Miguel, Carmen; Speed, Joshua S; Kasztan, Malgorzata et al. (2016) Endothelin-1 and the kidney: new perspectives and recent findings. Curr Opin Nephrol Hypertens 25:35-41
Heimlich, J Brett; Speed, Joshua S; O'Connor, Paul M et al. (2016) Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species. Br J Pharmacol 173:386-95
Davenport, Anthony P; Hyndman, Kelly A; Dhaun, Neeraj et al. (2016) Endothelin. Pharmacol Rev 68:357-418
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 159:20-9
Spradley, Frank T; Ho, Dao H; Pollock, Jennifer S (2016) Dahl SS rats demonstrate enhanced aortic perivascular adipose tissue-mediated buffering of vasoconstriction through activation of NOS in the endothelium. Am J Physiol Regul Integr Comp Physiol 310:R286-96
Guan, Zhengrong; Singletary, Sean T; Cha, Haword et al. (2016) Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats. Am J Physiol Renal Physiol 310:F456-65
Heimlich, J B; Speed, J S; Bloom, C J et al. (2015) ET-1 increases reactive oxygen species following hypoxia and high-salt diet in the mouse glomerulus. Acta Physiol (Oxf) 213:722-30
Su, Shaoyong; Wang, Xiaoling; Pollock, Jennifer S et al. (2015) Adverse childhood experiences and blood pressure trajectories from childhood to young adulthood: the Georgia stress and Heart study. Circulation 131:1674-81
Speed, Joshua S; Fox, Brandon M; Johnston, Jermaine G et al. (2015) Endothelin and renal ion and water transport. Semin Nephrol 35:137-44
Speed, Joshua S; Pollock, David M (2015) New clues towards solving the mystery of endothelin and blood pressure regulation. Hypertension 66:275-7

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