We propose to determine the distinct biological and chemical properties, and to pharmacologically manipulate the synthesis and actions of thromboxanes, endoperoxides, prostacyclins, and prostaglandins in several biological systems. 1. This proposal will attempt to delineate the intrinsic pathophysiological roles and interactions between components of the arachidonic acid metabolic pathway in blood vessels and platelets in the regulation and function of vascular tone and thrombosis. 2. We propose to establish (in intact animals) the selective vulnerability to inhibition of vascular prostacyclin production versus platelet thromboxane production. In addition, we intend to study the mechanism of action and utility of anti-thrombotic drugs. 3. We propose to study the potential role of intrinsic hydroperoxy fatty acids as modulators of prostacyclin synthesis and its impact in the regulation of vascular tone. 4. We will characterize the structural determinants for the fatty acid, prostaglandins, prostacyclin and thromboxane synthetic enzymes and for receptor recognition and activation in platelets and blood vessels. 5. Finally, we propose to continue our studies of the triene prostaglandins. We will also evaluate the role and potential of PGD3 as an anti-thrombotic agent, as well as characterize the utility and mechanism of eicosapentaenoate as a competitor of arachidonate on synthetic enzymes. Ultimately, we plan to utilize dietary manipulation to increase eicosapentaenoate and reduce arachidonate tissue and platelet levels in an attempt to manipulate in vivo platelet-blood vessel interactions such as thrombosis and vasospasms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL020787-11
Application #
3336260
Study Section
Biochemistry Study Section (BIO)
Project Start
1977-05-01
Project End
1990-04-30
Budget Start
1987-05-01
Budget End
1988-04-30
Support Year
11
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Tetsuka, T; Daphna-Iken, D; Miller, B W et al. (1996) Nitric oxide amplifies interleukin 1-induced cyclooxygenase-2 expression in rat mesangial cells. J Clin Invest 97:2051-6
Guan, Z; Tetsuka, T; Baier, L D et al. (1996) Interleukin-1 beta activates c-jun NH2-terminal kinase subgroup of mitogen-activated protein kinases in mesangial cells. Am J Physiol 270:F634-41
Rzymkiewicz, D M; Tetsuka, T; Daphna-Iken, D et al. (1996) Interleukin-1beta activates protein kinase C zeta in renal mesangial cells. Potential role in prostaglandin E2 up-regulation. J Biol Chem 271:17241-6
Thomas, M E; Morrison, A R; Schreiner, G F (1995) Metabolic effects of fatty acid-bearing albumin on a proximal tubule cell line. Am J Physiol 268:F1177-84
Tetsuka, T; Daphna-Iken, D; Srivastava, S K et al. (1995) Regulation of heme oxygenase mRNA in mesangial cells: prostaglandin E2 negatively modulates interleukin-1-induced heme oxygenase-1 mRNA. Biochem Biophys Res Commun 212:617-23
Rzymkiewicz, D M; DuMaine, J; Morrison, A R (1995) IL-1 beta regulates rat mesangial cyclooxygenase II gene expression by tyrosine phosphorylation. Kidney Int 47:1354-63
Tetsuka, T; Morrison, A R (1995) Tyrosine kinase activation is necessary for inducible nitric oxide synthase expression by interleukin-1 beta. Am J Physiol 269:C55-9
Daphna-Iken, D; Morrison, A R (1995) Interleukin-1 beta induces interstitial collagenase gene expression and protein secretion in renal mesangial cells. Am J Physiol 269:F831-7
Srivastava, S K; Tetsuka, T; Daphna-Iken, D et al. (1994) IL-1 beta stabilizes COX II mRNA in renal mesangial cells: role of 3'-untranslated region. Am J Physiol 267:F504-8
Rzymkiewicz, D; Leingang, K; Baird, N et al. (1994) Regulation of prostaglandin endoperoxide synthase gene expression in rat mesangial cells by interleukin-1 beta. Am J Physiol 266:F39-45

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