This proposal is designed to determine the contribution of endothelial ACE to 20-hydoxyeicosatetraenoic acid (20-HETE)-mediated vascular dysfunction in hypertension. 20-HETE and its biosynthetic enzymes (CYP4) have been linked to the development of hypertension in genetic and experimental animal models and recently in humans. The biology of 20-HETE in the vasculature parallels that of Ang II. Like Ang II, 20-HETE is a vasoconstrictor and a mitogen. Ang II actions in vascular cells including superoxide/ROS stimulation, NF-kB activation and induction of inflammatory molecules, are also shared by 20-HETE as our recent studies suggest. Preliminary data further indicated that 20-HETE is a potent inducer of ACE in endothelial cells. Moreover, in models of 20-HETE-dependent hypertension vascular expression of ACE and AT1R is highly increased and treatment with ACE inhibitors or ATI R blockers prevents or reverses 20-HETE-dependent hypertension. The proposed studies set forth a novel paradigm and an attractive hypothesis arguing that excessive production of 20-HETE within the vasculature (androgen-induced hypertension) leads to hypertension via mechanisms that include the induction of endothelial ACE, thus perpetuating an increase in vascular Ang II which, in turn and together with 20-HETE, promotes renal vascular dysfunction. The proposed studies will investigate the relationship between 20-HETE and ACE in hypertension, elucidate cellular mechanisms underiying 20-HETE-mediated ACE induction and examine the contribution of 20-HETE-ACE to the hypertensive vascular phenotype. Our preliminary findings are exciting and potentially of great significance as they bring into being a new face to an old paradigm and suggest a feed fonward amplification of vascular dysfunction and hypertension brought about by 20-HETE induction of ACE. This together with the identification of 20-HETE as the mediator of androgen-driven hypertension raises important questions regarding gender-specific RAS-androgen interactions. The importance of elucidating and understanding the mechanisms underiying 20-HETE pro-hypertensive actions is underscored by recent reports linking CYP4 polymorphism and 20-HETE levels to hypertension in humans.
Hypertension is a disease that leads to many manifestations including stroke, heart attack, and renal failure. It is recognized that men are at greater risk for hypertension than women and that androgen plays an important role. The mechanism of androgen-induced hypertension and susceptibility to cardiovascular morbidity is not completely known. Our studies identified 20-HETE as the mediator of androgen-induced hvpertension and have the potential to uncover novel therapeutic targets to treat hypertension.
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