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Regulation of cyclooxygenase by the heme-heme oxygenase system in microvessel endothelial cells
- Source :
- The Journal of pharmacology and experimental therapeutics. 300(1)
- Publication Year :
- 2001
-
Abstract
- 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 H(2), 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) E(2) and 6-keto-PGF(1alpha) levels. Exposure of cells to CoCl(2), 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 PGE(2) and 6-keto-PGF(1alpha) 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, PGE(2) and PGI(2), known to play a role in vascular homeostasis.
- Subjects :
- Hemeprotein
Prostaglandin
6-Ketoprostaglandin F1 alpha
Heme
Dinoprostone
Gene Expression Regulation, Enzymologic
chemistry.chemical_compound
Animals
Homeostasis
Humans
RNA, Messenger
Pharmacology
Regulation of gene expression
Biliverdin
biology
Chemistry
Blotting, Northern
Molecular biology
Epoprostenol
Capillaries
Heme oxygenase
Isoenzymes
Biochemistry
Prostaglandin-Endoperoxide Synthases
Heme Oxygenase (Decyclizing)
biology.protein
Microsome
Molecular Medicine
lipids (amino acids, peptides, and proteins)
Cyclooxygenase
Endothelium, Vascular
Rabbits
Subjects
Details
- ISSN :
- 00223565
- Volume :
- 300
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Accession number :
- edsair.doi.dedup.....db89b56630d18156264ceca47648ed81