title: Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase-derived PGD2 biosynthesis.
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.
authors.affiliation: Department of Regenerative Medicine and Advanced Cardiac Therapeutics, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Satori
authors.initials: S
authors.lastname: Tokudome
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Ken
authors.initials: K
authors.lastname: Shinmura
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuhashi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Morizane
authors.forename: Hidenori
authors.initials: H
authors.lastname: Moriyama
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tamaki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hayashida
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Noritada
authors.initials: N
authors.lastname: Yoshikawa
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimizu
authors.forename: Jin
authors.initials: J
authors.lastname: Endo
authors.forename: Takaharu
authors.initials: T
authors.lastname: Katayama
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Murata
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yuasa
authors.forename: Ruri
authors.initials: R
authors.lastname: Kaneda
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.forename: Naomi
authors.initials: N
authors.lastname: Eguchi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Koichiro
authors.initials: K
authors.lastname: Asano
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Utsunomiya
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005938:Glucocorticoids / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D054834:Lipocalins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D015230:Prostaglandin D2 / Q000096:biosynthesis*; D051381:Rats; D015398:Signal Transduction
chemical_list: D005938:Glucocorticoids; D054834:Lipocalins; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; D010100:Oxygen