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Vol. 300, Issue 1, 188-194, January 2002

Regulation of Cyclooxygenase by the Heme-Heme Oxygenase System in Microvessel Endothelial Cells

Asifa Haider, Rafal Olszanecki, Richard Gryglewski, Michal L. Schwartzman, Elias Lianos, Attallah Kappas, Alberto Nasjletti and Nader G. Abraham

New York Medical College, Department of Pharmacology, Valhalla, New York (A.H., M.L.S., A.N., N.G.A.); Jagiellonian University, Medical College, Department of Pharmacology, Cracow, Poland (R.O., R.G.); Robert Wood Johnson Medical School, New Brunswick, New Jersey (E.L.); and The Rockefeller University, New York, New York (A.K.)

Heme oxygenase (HO) is a microsomal enzyme that oxidatively cleaves heme to form biliverdin, with the release of iron and carbon monoxide (CO). HO not only controls the availability of heme for the synthesis of heme proteins but also is responsible for the generation of CO, which binds to the heme moiety of heme proteins thus affecting their enzymatic activity. Cyclooxygenase (COX) is a heme protein that catalyzes the conversion of arachidonic acid to prostaglandin H2, the precursor of prostanoids that participate in the regulation of vascular function. The goal of the present study was to determine whether the heme-HO system regulates COX enzyme expression and activity in vascular endothelial cells. Endothelial cells stably transfected with the human HO-1 gene exhibited a severalfold increase in human HO-1 mRNA levels, which was accompanied by an increase in HO activity and a marked decrease in prostaglandin (PG) E2 and 6-keto-PGF1alpha levels. Exposure of cells to CoCl2, an inducer of HO-1 gene expression, resulted in increases in HO-1 protein levels and HO activity. The increase in HO activity was associated with a subsequent decrease in COX activity, which returned to normal levels following normalization of HO activity. The addition of heme resulted in an increase in COX activity with an increase in PGE2 and 6-keto-PGF1alpha levels. The degree of HO-1 expression and, consequently, the level of cellular heme, were directly related to COX activity. These results demonstrate that the heme-HO system can function as a cellular regulator of the expression of vascular COX, thus influencing the generation of prostanoids, PGE2 and PGI2, known to play a role in vascular homeostasis.


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Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics



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