The overall objective of this application is to study the incorporation, release, metabolism and biological activities of a vascular derived cytochrome P450 (Cyto P-450) metabolite of arachidonic acid (AA)L 14, 15- eicosatrienoic acid (14, 15-EET). Experiments are designed to further characterize their vascular and renal actions and potential role in the regulation of blood pressure. Recent reports demonstrated that 14, 15 EET was the preferred EET that incorporated into tissue phospholipids. Because of the fact that oxygenated PLs are better substrates for Phospholipase A2 (PLA2), the incorporation of 14, 15-EET into PLs may represent a storage form of cyto P-450 metabolites of AA in the membrane PLs compartment which can be released upon tissue injury and hormonal or cytokines stimulation. 14, 15-EET and its metabolite had been found to have potent biological activities. It inhibits platelet aggregation, vasopressin (AVP) induced antiduresis and renin release. It also lowered the blood pressure of normal and hypertensive rats. Since it inhibits the cycloxygenase activity 14, 15-EET may cause shunting of the metabolism of AA to the lipoxygenases or to the cyto P-450 pathway. Little is known about the mechanism and modulation of the secondary metabolism of EETs by other oxygenases and the possible conjugation with glutathione. Secondary metabolism of 14, 15-EET in blood vessels and kidney will be studied in the tissue and cellular levels. The endogenous level of 14, 15-EET and its metabolites in these tissues will be identified by GC/MS. The incorporation of 14, 15-EET into lyso-PAF for the generation of 14, 15-EET-PAF will be investigated. Synthetic compounds of the biologically active metabolites of 14, 15-EET and 14, 15-EET-PAF will be available for study. The possibility that 14, 15-EET or its metabolites may function through its own receptors or receptors of other mediators will be investigated. Results of these studies will provide new information on fundamental concepts on the storage, release, transformation and the physiological functions of this cyto P-450 metabolite of AA in vasculature and renal system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025316-14
Application #
3338034
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1989-09-01
Project End
1993-12-31
Budget Start
1993-07-01
Budget End
1993-12-31
Support Year
14
Fiscal Year
1993
Total Cost
Indirect Cost
Name
New York Medical College
Department
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Wong, P Y; Lai, P S; Falck, J R (2000) Mechanism and signal transduction of 14 (R), 15 (S)-epoxyeicosatrienoic acid (14,15-EET) binding in guinea pig monocytes. Prostaglandins Other Lipid Mediat 62:321-33
Liu, P; Yin, K; Nagele, R et al. (1998) Inhibition of nitric oxide synthase attenuates peroxynitrite generation, but augments neutrophil accumulation in hepatic ischemia-reperfusion in rats. J Pharmacol Exp Ther 284:1139-46
Yin, K; Hock, C E; Tahamont, M et al. (1998) Time-dependent cardiovascular and inflammatory changes in acute endotoxemia. Shock 9:434-42
Lin, K T; Xue, J Y; Lin, M C et al. (1998) Peroxynitrite induces apoptosis of HL-60 cells by activation of a caspase-3 family protease. Am J Physiol 274:C855-60
Hock, C E; Yin, K; Yue, G et al. (1997) Effects of inhibition of nitric oxide synthase by aminoguanidine in acute endotoxemia. Am J Physiol 272:H843-50
Wong, P Y; Lai, P S; Shen, S Y et al. (1997) Post-receptor signal transduction and regulation of 14(R),15(S)-epoxyeicosatrienoic acid (14,15-EET) binding in U-937 cells. J Lipid Mediat Cell Signal 16:155-69
Yue, G; Sun, F F; Dunn, C et al. (1996) The 21-aminosteroid tirilazad mesylate can ameliorate inflammatory bowel disease in rats. J Pharmacol Exp Ther 276:265-70
Lin, K T; Dudhane, A; Godfrey, H P et al. (1996) Identification and characterization of a high-affinity leukotriene B4 receptor on guinea pig T lymphocytes and its regulation by lipoxin A4. J Pharmacol Exp Ther 277:679-84
Liu, P; Yin, K; Yue, G et al. (1995) Role of nitric oxide in hepatic ischemia-reperfusion with endotoxemia. J Inflamm 46:144-54
Pritchard Jr, K A; O'Banion, M K; Miano, J M et al. (1994) Induction of cyclooxygenase-2 in rat vascular smooth muscle cells in vitro and in vivo. J Biol Chem 269:8504-9

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