Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 2, Pages 1179-1188Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M706839200
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- NCRR NIH HHS [RR-023567] Funding Source: Medline
- NHLBI NIH HHS [HL R01 073278, HL 83799] Funding Source: Medline
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Prostaglandin D-2 (PGD(2)) is a cyclooxygenase (COX) product of arachidonic acid that activates D prostanoid receptors to modulate vascular, platelet, and leukocyte function in vitro. However, little is known about its enzymatic origin or its formation in vivo in cardiovascular or inflammatory disease.11,15-Dioxo-9 alpha-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM) was identified by mass spectrometry as a metabolite of infused PGD2 that is detectable in mouse and human urine. Using liquid chromatography-tandem mass spectrometry, tetranor PGDM was much more abundant than the PGD(2) metabolites, 11 beta-PGF(2 alpha) and 2,3-dinor-11 beta-PGF(2 alpha), in human urine and was the only endogenous metabolite detectable in mouse urine. Infusion of PGD2 dose dependently increased urinary tetranor PGDM > 2,3-dinor-11 beta-PGF(2 alpha) > 11 beta-PGF(2 alpha) in mice. Deletion of either lipocalin-type or hemopoietic PGD synthase enzymes decreased urinary tetranor PGDM. Deletion or knockdown of COX-1, but not deletion of COX-2, decreased urinary tetranor PGDM in mice. Correspondingly, both PGDM and 2,3-dinor-11 beta-PGF(2 alpha) were suppressed by inhibition of COX-1 and COX-2, but not by selective inhibition of COX-2 in humans. PGD2 has been implicated in both the development and resolution of inflammation. Administration of bacterial lipopolysaccharide coordinately elevated tetranor PGDM and 2,3-dinor-11 beta-PGF(2 alpha) in volunteers, coincident with a pyrexial and systemic inflammatory response, but both metabolites fell during the resolution phase. Niacin increased tetranor PGDM and 2,3-dinor-11 beta-PGF(2 alpha), in humans coincident with facial flushing. Tetranor PGDM is an abundant metabolite in urine that reflects modulated biosynthesis of PGD(2) in humans and mice.
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