Role of 20-HETE in Endothelial Dysfunction

New York Medical College, Valhalla NY

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Abstract

This is a proposal to investigate the function and regulation of 20-hydroxyeicosatetraenoic acid (20-[unreadable] HETE) synthesis in the vasculature, more specifically, its participation in endothelium dysfunction in[unreadable] models of increased vascular expression of cytochrome P450 (CYP) 4A. 20-HETE is a primary[unreadable] eicosanoid in the microcirculation where it participates in the regulation of vascular tone. In rat renal[unreadable] arteries, CYP4A expression and 20-HETE production increased with decreased arterial diameter.[unreadable] CYP4A overexpression in small arteries and arterioles increased vascular reactivity and myogenic tone.[unreadable] Recent studies and preliminary results suggest that the endothelium is a target for 20-HETE bioactions.[unreadable] Smooth muscle-specific CYP4A1 expression via Ad-SM22-4A1 induces a marked CYP4A-dependent[unreadable] and 20-HETE-mediated endothelial sprouting in renal arterial microvessels. In vitro, 20-HETE is a[unreadable] potent angiogenic factor stimulating capillary-like tube formation of endothelial cells by a mechanism[unreadable] that may include MAPK activation and induction of inflammatory and angiogenic proteins (IL-8 and[unreadable] VEGF). In vivo, intravenous injection of Adv-CYP4A2 causes hypertension and renal arteries from[unreadable] these rats display endothelial dysfunction, which can be reversed by inhibition of CYP4A activity.[unreadable] Arteries from Adv-CYP4A2-transduced rats produce more 20-HETE and less NO; they also express[unreadable] higher levels of inflammatory proteins (ICAM and VCAM). These findings raise the possibility that[unreadable] vascular 20-HETE is an important determinant of endothelial dysfunction, a condition that is[unreadable] characterized by decreased NO bioavailability and enhanced endothelial activation, and are the basis[unreadable] for the proposal's hypothesis: Vascular overexpression of CYP4A fosters prohypertensive[unreadable] mechanisms via increased production of 20-HETE in a manner that may include endothelial[unreadable] dysfunction and activation. This hypothesis will be tested by 1) determining the relationship between[unreadable] hypertension, endothelial dysfunction and activation, CYP4A expression and 20-HETE synthesis; 2)[unreadable] determining whether the functional consequences of increased vascular expression of CYP4A is[unreadable] associated with endothelial expression and synthesis of CYP4A and 20-HETE, respectively; and 3)[unreadable] exploring mechanisms underlying 20-HETE mediated endothelial dysfunction and activation.