This is a proposal to investigate the mechanisms underlying 20-hydroxyeicosatetraenoic acid (20-HETE)- mediated androgen-induced (male-specific) hypertension. Hypertension is a complex process that involves cardiac output and total peripheral resistance, which is mainly manifested by the small arteries and arterioles due to increase in smooth muscle constriction, endothelial dysfunction, and endothelial activation. 20-HETE is a primary eicosanoid in the microcirculation where it participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor stimuli and contributes to myogenic, mitogenic and angiogenic responses. We have demonstrated that androgen-induced hypertension in rats is driven by increased synthesis of 20-HETE in the vasculature. Moreover, renal arteries from androgen treated-rats displayed endothelial dysfunction that is characterized by reduction in NO bioavailability. In vitro, 20- HETE causes endothelial dysfunction via eNOS uncoupling and endothelial activation (increased inflammatory cytokines) via NFkB activation. These findings suggest that vascular 20-HETE is an important determinant of androgen-induced hypertension through action on both endothelial dysfunction and endothelial activation and are the basis for our working hypothesis: Androgen-induced hypertension is mediated by increased vascular 20-HETE, which, in turn, induces endothelial dysfunction and endothelial activation, each of which contributes to the genesis of hypertension. To this end, it is unclear whether the activation of both pathways by 20-HETE is required simultaneously to produce hypertension or whether a single pathway is either sufficient or more dominant. This proposal will discern the temporal relationship between these two processes and will examine the contribution of each to 20-HETE-mediated male-specific hypertension using 1) pharmacological (enzyme inhibitors) and molecular/genetic (viral vectors and transgenic mouse models) to inhibit or induce the synthesis of 20-HETE;and 2) inhibitors of NFkB activation and transgenic mice in which NFkB activation is impaired to determine whether androgen-induced, 20- HETE-driven hypertension is co-dependent upon both endothelial activation and dysfunction. It is recognized that men are at greater risks for hypertension and cardiovascular disease than women and that androgen plays an important role. The proposed studies have the potential of providing insights into mechanisms underlying the increase prevalence of hypertension and susceptibility to cardiovascular morbidity in male and thereby uncovering a novel therapeutic target for the treatment of hypertension driven by increased androgen levels.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL097402-04
Application #
8311667
Study Section
Special Emphasis Panel (ZRG1-F10-S (21))
Program Officer
Meadows, Tawanna
Project Start
2009-08-01
Project End
2013-05-24
Budget Start
2012-08-01
Budget End
2013-05-24
Support Year
4
Fiscal Year
2012
Total Cost
$43,506
Indirect Cost
Name
New York Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Wu, Cheng-Chia; Gupta, Tanush; Garcia, Victor et al. (2014) 20-HETE and blood pressure regulation: clinical implications. Cardiol Rev 22:1-12
Wu, Cheng-Chia; Mei, Shaojun; Cheng, Jennifer et al. (2013) Androgen-sensitive hypertension associates with upregulated vascular CYP4A12-20-HETE synthase. J Am Soc Nephrol 24:1288-96
Ding, Yan; Wu, Cheng-Chia; Garcia, Victor et al. (2013) 20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension. Am J Physiol Renal Physiol 305:F753-63
Wu, Cheng-Chia; Cheng, Jennifer; Zhang, Frank Fan et al. (2011) Androgen-dependent hypertension is mediated by 20-hydroxy-5,8,11,14-eicosatetraenoic acid-induced vascular dysfunction: role of inhibitor of kappaB Kinase. Hypertension 57:788-94
Wu, Cheng-Chia; Schwartzman, Michal Laniado (2011) The role of 20-HETE in androgen-mediated hypertension. Prostaglandins Other Lipid Mediat 96:45-53
Sodhi, Komal; Wu, Cheng-Chia; Cheng, Jennifer et al. (2010) CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid- and angiotensin II-dependent. Hypertension 56:871-8