EP2 receptor activation by prostaglandin E2 leads to induction of HO-1 via PKA and PI3K pathways in C6 cells.
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.
Park
Min Kyu
MK
Department of Pharmacology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, 92 Chilam Dong, Jinju 660-751, Republic of Korea.
Kang
Young Jin
YJ
Ha
Yu Mi
YM
Jeong
Jae Ju
JJ
Kim
Hye Jung
HJ
Seo
Han Geuk
HG
Lee
Jae Heun
JH
Chang
Ki Churl
KC
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
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