This Program Project Grant proposal aims at investigating the function and regulation of cytochrome P450 (CYP)-derived eicosanoids in relation to vascular and renal mechanism of blood pressure control. The proposal focuses on vascular and/or renal mechanisms involving 20-hydroxyeicosatetraenoic acid (20-HETE), CYP2E1-derived 19(R)- and 18(R)-HETE, and epoxyeicosatrienoic acids (EETs) of both the cis-EET and trans-EET configuration. The experimental strategies combine molecular, cellular, isolated organ and whole animal approaches. The proposed research activities are organized into four projects supported by three cores. Project 1 investigates the role of CYP2E1-derived eicosanoids in the regulation of vascular reactivity and blood pressure. Blood pressure and vascular reactivity to constrictor stimuli will be studied in relation to vascular synthesis of CYP2E1-derived eicosanoids and 20-HETE in animals subjected to interventions that increase (CYP2E1 gene transfer) or decrease (CYP2E1 inhibition;CYP2E1-null mice) the synthesis of CYP2E1-derived eicosanoids. Project 2 investigates the role of 20-HETE as a determinant of endothelial cell dysfunction and activation in rats made hypertensive by in vivo CYP4A2 gene transfer. Relationships will be examined between vascular 20-HETE production, indices of endothelial dysfunction, and blood pressure. The contribution of endothelial versus smooth muscle 20-HETE will be assessed. The molecular mechanisms of 20-HEETE-induced endothelial dysfunction will be addressed. Project 3 will investigate the role of EETs in regulation of Na transport in the cortical collecting duct (CCD). The EETs-dependent effects of arachidonic acid and adenosine on ENaC will be studied as a function of Na intake and epoxygenase expression. The signaling mechanisms underlying the inhibitory action of EETs on ENaC will be defined. Project 4 will study the renal synthesis and release of cis- and trans-EETs in relation to pressure and oxidative stress, examine their vasoregulatory actions, and determine the relative contribution of cis and trans-EETs to the exaggerated renal vasodilatory effect of arachidonic acid in SHR. Core A provides administrative support. Core B is responsible for measurement of eicosanoids by mass spectrometry. Core C provides viral vectors to transfer CYP genes in the sense and antisense orientation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL034300-25
Application #
7674730
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Thrasher, Terry N
Project Start
1997-09-01
Project End
2011-04-14
Budget Start
2009-09-01
Budget End
2011-04-14
Support Year
25
Fiscal Year
2009
Total Cost
$2,464,863
Indirect Cost
Name
New York Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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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