20-HETE-Dependent Hypertension: Role of RAS

$447,563P01FY2011HLNIH

New York Medical College, Valhalla NY

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Abstract

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.

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