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Vol. 300, Issue 1, 188-194, January 2002
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-PGF1
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-PGF1
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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