Human cytochrome P450 2J2 (CYP2J2) oxidatively metabolizes arachidonic acid (AA) in endothelial cells to epoxyeicosatrienoic acids (EETs). The EETs possess potent vasodilatory and anti-inflammatory effects in the coronary microcirculation and peripheral vasculature, and may serve as an important reserve system to nitric oxide. However, the physiological functions of this pathway have not been well characterized in whole animal models or humans. Since impairment in the nitric oxide system is observed in patients with cardiovascular disease and """"""""endothelial dysfunction"""""""" contributes significantly to disease pathogenesis, endothelial CYP2J2 activity may be clinically important. Single nucleotide polymorphisms in the gene encoding CYP2J2 have been identified recently, and may play an integral role in the development and progression of cardiovascular disease. In order to characterize the physiological functions of CYP2J2 in the vasculature, and evaluate the potential clinical importance of this metabolic pathway in patients with cardiovascular disease, this proposal aims to: (1) develop a transgenic mouse model with endothelial-specific overexpression of human CYP2J2 using the murine Tie2 promoter, (2) characterize the in vivo effects of constitutively increased, CYP2J2-mediated endothelial EET biosynthesis on the regulation of blood pressure and intravascular inflammation in these mice, and (3) determine if polymorphisms in the gene encoding CYP2J2 influence the development and/or progression of atherosclerotic disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES012856-02
Application #
6806488
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Humble, Michael C
Project Start
2003-09-30
Project End
2006-09-29
Budget Start
2004-09-30
Budget End
2005-09-29
Support Year
2
Fiscal Year
2004
Total Cost
$53,092
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Lee, C R; North, K E; Bray, M S et al. (2008) Cyclooxygenase polymorphisms and risk of cardiovascular events: the Atherosclerosis Risk in Communities (ARIC) study. Clin Pharmacol Ther 83:52-60
Lee, Craig R; North, Kari E; Bray, Molly S et al. (2007) CYP2J2 and CYP2C8 polymorphisms and coronary heart disease risk: the Atherosclerosis Risk in Communities (ARIC) study. Pharmacogenet Genomics 17:349-58
Lee, Craig R; Bottone Jr, Frank G; Krahn, Joseph M et al. (2007) Identification and functional characterization of polymorphisms in human cyclooxygenase-1 (PTGS1). Pharmacogenet Genomics 17:145-60
Lee, Craig R; North, Kari E; Bray, Molly S et al. (2006) Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Hum Mol Genet 15:1640-9
Seubert, John M; Sinal, Christopher J; Graves, Joan et al. (2006) Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. Circ Res 99:442-50
Lee, Craig R; North, Kari E; Bray, Molly S et al. (2006) NOS3 polymorphisms, cigarette smoking, and cardiovascular disease risk: the Atherosclerosis Risk in Communities study. Pharmacogenet Genomics 16:891-9
Fornage, Myriam; Lee, Craig R; Doris, Peter A et al. (2005) The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke. Hum Mol Genet 14:2829-37