title: EP2 receptor activation by prostaglandin E2 leads to induction of HO-1 via PKA and PI3K pathways in C6 cells.
abstract: Recently we proposed that COX-2 induction precedes expression of HO-1 in ischemic preconditioned rat brain. In the current study, we investigated the molecular mechanism by which prostaglandin E(2), one of COX-2 metabolites, induces HO-1 in rat C6 brain cells. We demonstrated that concentration of PGE(2) increased HO-1 expression in C6 cells in vitro. The effects of PGE(2) were mimicked by PGE(2) receptor EP(2) agonists, 11-deoxy PGE(2), and cAMP analog, dibutyl-cAMP. HO-1 expression by PGE(2) was inhibited by LY294002, PI3K inhibitor and H89, PKA inhibitor. The EP(2)-specific antagonist, AH8006 also inhibited PGE(2)-mediated HO-1 expression in a concentration-dependent manner. Finally, PGE(2) inhibited GOX-induced apoptosis as assayed by FACS analysis or DNA strand breaks assay, and this cell death was reversed by ZnPPIX, HO-1 inhibitor. In addition to HO-1 induction, PGE(2) also increased phosphorylation of Bad by PKA- and PI3K-depednent manner. Taken together, we conclude that PGE(2) induces HO-1 protein expression through PKA and PI3K signaling pathways via EP(2) receptor in C6 cells. The induction of HO-1 along with increase of p-Bad by PGE(2) is responsible for anti-apoptosis against oxidant stress.
authors.affiliation: Department of Pharmacology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, 92 Chilam Dong, Jinju 660-751, Republic of Korea.
authors.forename: Min Kyu
authors.initials: MK
authors.lastname: Park
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Kang
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Ha
authors.forename: Jae Ju
authors.initials: JJ
authors.lastname: Jeong
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
authors.forename: Jae Heun
authors.initials: JH
authors.lastname: Lee
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D011524:Protoporphyrins; C545646:Ptger2 protein, rat; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051025:bcl-Associated Death Protein; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone