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J. Biol. Chem., Vol. 279, Issue 4, 2648-2656, January 23, 2004

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20-Hydroxyeicosatetraenoic Acid (20-HETE) Metabolism in Coronary Endothelial Cells^*

Terry L. Kaduce, Xiang Fang, Shawn D. Harmon, Christine L. Oltman, Kevin C. Dellsperger¶, Lynn M. Teesch||, V. Raj Gopal**, J. R. Falck**, William B. Campbell, Neal L. Weintraub, and Arthur A. Spector

From the Departments of Biochemistry and Internal Medicine, Carver College of Medicine, and the ^||High Resolution Mass Spectrometry Facility, University of Iowa, Iowa City, Iowa 52242, the ^¶Department of Internal Medicine, University of Missouri, Columbia, Missouri 65212, the ^**Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

We have investigated the role of endothelial cells in the metabolism of 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoactive mediator synthesized from arachidonic acid by cytochrome P450 -oxidases. Porcine coronary artery endothelial cells (PCEC) incorporated 20-[³H]HETE primarily into the sn-2 position of phospholipids through a coenzyme A-dependent process. The incorporation was reduced by equimolar amounts of arachidonic, eicosapentaenoic or 8,9-epoxyeicosatrienoic acids, but some uptake persisted even when a 10-fold excess of arachidonic acid was available. The retention of 20-[³H]HETE increased substantially when methyl arachidonoyl fluorophosphonate, but not bromoenol lactone, was added, suggesting that a Ca²⁺-dependent cytosolic phospholipase A₂ released the 20-HETE contained in PCEC phospholipids. Addition of calcium ionophore A23187 produced a rapid release of 20-[³H]HETE from the PCEC, a finding that also is consistent with a Ca²⁺-dependent mobilization process. PCEC also converted 20-[³H]HETE to 20-carboxy-arachidonic acid (20-COOH-AA) and 18-, 16-, and 14-carbon -oxidation products. 20-COOH-AA produced vasodilation in porcine coronary arterioles, but 20-HETE was inactive. These results suggest that the incorporation of 20-HETE and its subsequent conversion to 20-COOH-AA in the endothelium may be important in modulating coronary vascular function.

Received for publication, June 26, 2003 , and in revised form, October 29, 2003.

^* This study was supported by National Institutes of Health Grants HL72845 (to A. A. S.), HL62984 and HL070860 (to N. L. W.), HL51055 (to W. B. C.), GM31278 (to J. R. F.), and Shared Instrumentation Grant RR 13799. Support also was provided by American Heart Association Research Grant 0230096N (to X. F.), Department of Veterans Affairs Merit Review Entry Program Grant (to C. L. O.) and Merit Review Award (to K. C. D.), and the Robert A. Welch Foundation (to J. R. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry, 4-403 BSB, University of Iowa, 51 Newton Rd, Iowa City, IA 52242. Tel.: 319-335-7913; Fax: 319-335-9570; E-mail: arthurspector{at}uiowa.edu.

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