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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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New York Medical College
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Elijovich, Fernando; Milne, Ginger L; Brown, Nancy J et al. (2018) Two Pools of Epoxyeicosatrienoic Acids in Humans: Alterations in Salt-Sensitive Normotensive Subjects. Hypertension 71:346-355
Rocic, Petra; Schwartzman, Michal Laniado (2018) 20-HETE in the regulation of vascular and cardiac function. Pharmacol Ther 192:74-87
Singh, S P; McClung, J A; Bellner, L et al. (2018) CYP-450 Epoxygenase Derived Epoxyeicosatrienoic Acid Contribute To Reversal of Heart Failure in Obesity-Induced Diabetic Cardiomyopathy via PGC-1 ? Activation. Cardiovasc Pharm Open Access 7:
Schragenheim, Joseph; Bellner, Lars; Cao, Jian et al. (2018) EET enhances renal function in obese mice resulting in restoration of HO-1-Mfn1/2 signaling, and decrease in hypertension through inhibition of sodium chloride co-transporter. Prostaglandins Other Lipid Mediat 137:30-39
Soler, Amanda; Hunter, Ian; Joseph, Gregory et al. (2018) Elevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation. J Mol Cell Cardiol 117:88-99
Garcia, Victor; Gilani, Ankit; Shkolnik, Brian et al. (2017) 20-HETE Signals Through G-Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. Circ Res 120:1776-1788
Sodhi, Komal; Srikanthan, Krithika; Goguet-Rubio, Perrine et al. (2017) pNaKtide Attenuates Steatohepatitis and Atherosclerosis by Blocking Na/K-ATPase/ROS Amplification in C57Bl6 and ApoE Knockout Mice Fed a Western Diet. Sci Rep 7:193
Wang, Lijun; Zhang, Chengbiao; Su, Xiao-Tong et al. (2017) PGF2?regulates the basolateral K channels in the distal convoluted tubule. Am J Physiol Renal Physiol 313:F254-F261
Zhang, Hui; Falck, John R; Roman, Richard J et al. (2017) Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen-Glucose Deprivation in Cortical Neurons. Cell Mol Neurobiol 37:1279-1286
Pandey, Varunkumar; Garcia, Victor; Gilani, Ankit et al. (2017) The Blood Pressure-Lowering Effect of 20-HETE Blockade in Cyp4a14(-/-) Mice Is Associated with Natriuresis. J Pharmacol Exp Ther 363:412-418

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