Vasoregulatory Function of CYP2E1-Derived Eicosanoids

New York Medical College, Valhalla NY

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Abstract

This is a proposal to investigate the role played by cytochrome P450 2E1 (CYP2E1 )-deriyed[unreadable] eicosanoids in the regulation of vasoconstrictor responsiveness and blood pressure in rats and mice.[unreadable] The proposal focuses on CYP2E1-dependent vascular production of 19(R)- and 18(R)-[unreadable] hydroxyeicosatetraenoic acids (HETE), the vasoregulatory action of such eicosanoids and their[unreadable] interaction with 20-HETE, and the notion that 19(R)- and 18(R)-HETE subserve antihypertensive[unreadable] functions by interfering with 20-HETE-induced sensitization of vascular smooth muscle to constrictor[unreadable] stimuli. The following aims will be addressed. AIM 1: To test the hypothesis that high blood pressure[unreadable] elicits reduction of vascular CYP2E1 and synthesis of 19(R)- and 18(R)-HETE, with attendant[unreadable] amplification of 20-HETE-induced sensitization to constrictor stimuli bringing about augmentation of[unreadable] vascular reactivity. Studies will be conducted in SHR, in rats made hypertensive by treatment with[unreadable] deoxycorticosterone or angiotensin II, and in normotensive controls. We seek to determine[unreadable] relationships between the level of blood pressure, vascular CYP2E1 expression and reactivity to[unreadable] constrictor stimuli as affected by 20-HETE and CYP2E1-derived eicosanoids. AIM 2: To test the[unreadable] hypothesis that gender, dietary potassium and dietary sodium influence vascular CYP2E1 expression[unreadable] and synthesis of 19(R)- and 18(R)-HETE, with consequential alterations in constrictor responsiveness[unreadable] resulting from changes in the effectiveness of the 20-HETE-dependent mechanism of vascular[unreadable] sensitization to constrictor stimuli. We will explore relationships between vascular CYP4A and CYP2E1[unreadable] expression, synthesis of 20-, 19(R)- and 18(R)-HETE, and responsiveness to constrictor stimuli as a[unreadable] function of gender and dietary potassium and sodium. AIM 3: To test the hypothesis that upregulation[unreadable] of vascular CYP2E1 expression and synthesis of 19(R)- and 18(R)-HETE attenuates the development[unreadable] of hypertension. The effects of CYP2E1 gene transfer on blood pressure, vascular CYP2E1 and[unreadable] synthesis of CYP-derived eicosanoids, and reactivity of the vasculature to constrictor stimuli will be[unreadable] explored in SHR, and rats made hypertensive by angiotensin II infusion or injection of an adenoviral[unreadable] construct expressing CYP4A2. AIM 4: To test the hypothesis that reduction of vascular CYP2E1[unreadable] activity and/or expression promotes elevation of blood pressure. We seek to determine whether blood[unreadable] pressure and blood pressure responsiveness to angiotensin II infusion are enhanced in rats[unreadable] undergoing inhibition of CYP2E1, and in CYP2E1-null mice.