Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase-derived PGD2 biosynthesis.

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
      Original Publication: New Haven [etc.] American Society for Clinical Investigation.
    • Subject Terms:
      Glucocorticoids/*pharmacology ; Heart/*drug effects ; Intramolecular Oxidoreductases/*metabolism ; Lipocalins/*metabolism ; Myocardial Reperfusion Injury/*metabolism ; Prostaglandin D2/*biosynthesis; Animals ; Cells, Cultured ; Cyclooxygenase 2/genetics ; Cyclooxygenase 2/metabolism ; Enzyme Activation ; Hypoxia/genetics ; Hypoxia/metabolism ; Mice ; Mice, Knockout ; Myocardial Reperfusion Injury/genetics ; Myocardial Reperfusion Injury/pathology ; Oxygen/metabolism ; Rats ; Signal Transduction
    • Abstract:
      Lipocalin-type prostaglandin D synthase (L-PGDS), which was originally identified as an enzyme responsible for PGD2 biosynthesis in the brain, is highly expressed in the myocardium, including in cardiomyocytes. However, the factors that control expression of the gene encoding L-PGDS and the pathophysiologic role of L-PGDS in cardiomyocytes are poorly understood. In the present study, we demonstrate that glucocorticoids, which act as repressors of prostaglandin biosynthesis in most cell types, upregulated the expression of L-PGDS together with cytosolic calcium-dependent phospholipase A2 and COX2 via the glucocorticoid receptor (GR) in rat cardiomyocytes. Accordingly, PGD2 was the most prominently induced prostaglandin in vivo in mouse hearts and in vitro in cultured rat cardiomyocytes after exposure to GR-selective agonists. In isolated Langendorff-perfused mouse hearts, dexamethasone alleviated ischemia/reperfusion injury. This cardioprotective effect was completely abrogated by either pharmacologic inhibition of COX2 or disruption of the gene encoding L-PGDS. In in vivo ischemia/reperfusion experiments, dexamethasone reduced infarct size in wild-type mice. This cardioprotective effect of dexamethasone was markedly reduced in L-PGDS-deficient mice. In cultured rat cardiomyocytes, PGD2 protected against cell death induced by anoxia/reoxygenation via the D-type prostanoid receptor and the ERK1/2-mediated pathway. Taken together, these results suggest what we believe to be a novel interaction between glucocorticoid-GR signaling and the cardiomyocyte survival pathway mediated by the arachidonic acid cascade.
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    • Accession Number:
      0 (Glucocorticoids)
      0 (Lipocalins)
      EC 1.14.99.1 (Cyclooxygenase 2)
      EC 5.3.- (Intramolecular Oxidoreductases)
      EC 5.3.99.2 (prostaglandin R2 D-isomerase)
      RXY07S6CZ2 (Prostaglandin D2)
      S88TT14065 (Oxygen)
    • Publication Date:
      Date Created: 20090520 Date Completed: 20090724 Latest Revision: 20220311
    • Publication Date:
      20250114
    • Accession Number:
      PMC2689117
    • Accession Number:
      10.1172/JCI37413
    • Accession Number:
      19451694