Oxidative Damage of Cardiomyocytes Is Limited by Extracellular Regulated Kinases 1/2-mediated Induction of Cyclooxygenase-2

Oxidative stress causes cardiac damage following ischemia/reperfusion and in response to anthracyclines. Extracellular signal-regulated kinases (ERK) 1/2 are activated by oxidative stress in cardiac myocytes and protect cardiac myocytes from apoptosis. Prostaglandins (PG) also protect cells from injury in a number of tissues, including the cardiomyocyte. Cyclooxygenase (COX) the rate-limiting enzyme in PG biosynthesis has two isoforms, the constitutive COX-1 and an inducible COX-2. Here, we examined the effects of two oxidative stresses, hydrogen peroxide (H2O2) and the anthracycline doxorubicin on the activity of ERK1/2 and the expression of COX isoforms and PG formation in neonatal rat primary cardiomyocytes. These cells expressed COX-1 at rest and both COX isoforms on treatment with phorbol 12-myristate 13-acetate. Exposure to 50 μmH2O2 for 10 min or doxorubicin at 10 and 100 μg/ml caused expression of COX-2 that was prevented by free radical scavengers. COX-2 induction was associated with activation of ERK1/2 and the specific ERK-inhibitor PD098059 abolished COX-2 expression. Treatment of cells with decoy oligonucleotides corresponding to COX-2 promoter elements implicated the AP-1 and NF-κB-2 but not the NF-κB-1 in the transcription of COX-2. Induction of COX-2 mRNA and protein was accompanied by increased prostacyclin formation, which was abolished by the selective COX-2 inhibitor, NS-398, and PD098059. H2O2 and doxorubicin enhanced the release of lactate dehydrogenase and free radical scavengers prevented this. NS-398 enhanced the release of lactate dehydrogenase in response to H2O2 and doxorubicin, whereas the injury was prevented by iloprost, a stable prostacyclin analogue. In cardiomyocytes cell injury by H2O2 and doxorubicin is limited by an increase in prostacyclin formation that reflects induction of COX-2 mediated by ERK1/2 activation. Oxidative stress causes cardiac damage following ischemia/reperfusion and in response to anthracyclines. Extracellular signal-regulated kinases (ERK) 1/2 are activated by oxidative stress in cardiac myocytes and protect cardiac myocytes from apoptosis. Prostaglandins (PG) also protect cells from injury in a number of tissues, including the cardiomyocyte. Cyclooxygenase (COX) the rate-limiting enzyme in PG biosynthesis has two isoforms, the constitutive COX-1 and an inducible COX-2. Here, we examined the effects of two oxidative stresses, hydrogen peroxide (H2O2) and the anthracycline doxorubicin on the activity of ERK1/2 and the expression of COX isoforms and PG formation in neonatal rat primary cardiomyocytes. These cells expressed COX-1 at rest and both COX isoforms on treatment with phorbol 12-myristate 13-acetate. Exposure to 50 μmH2O2 for 10 min or doxorubicin at 10 and 100 μg/ml caused expression of COX-2 that was prevented by free radical scavengers. COX-2 induction was associated with activation of ERK1/2 and the specific ERK-inhibitor PD098059 abolished COX-2 expression. Treatment of cells with decoy oligonucleotides corresponding to COX-2 promoter elements implicated the AP-1 and NF-κB-2 but not the NF-κB-1 in the transcription of COX-2. Induction of COX-2 mRNA and protein was accompanied by increased prostacyclin formation, which was abolished by the selective COX-2 inhibitor, NS-398, and PD098059. H2O2 and doxorubicin enhanced the release of lactate dehydrogenase and free radical scavengers prevented this. NS-398 enhanced the release of lactate dehydrogenase in response to H2O2 and doxorubicin, whereas the injury was prevented by iloprost, a stable prostacyclin analogue. In cardiomyocytes cell injury by H2O2 and doxorubicin is limited by an increase in prostacyclin formation that reflects induction of COX-2 mediated by ERK1/2 activation. Reperfusion of ischemic myocardium results in an abrupt aggravation of cardiomyocyte injury, demonstrated experimentally by the re-introduction of oxygen into hypoxic myocardium (1Hearse D.J. Humphrey S.M. Nayler W.G. Slade A. Border D. J. Mol. Cell. Cardiol. 1975; 7: 315-324Abstract Full Text PDF PubMed Scopus (176) Google Scholar). This injury is due in part to the generation of reactive oxygen species (2Zweier J.L. J. Biol. Chem. 1988; 263: 1353-1357Abstract Full Text PDF PubMed Google Scholar, 3Bolli R. Patel B.S. Jeroudi M.O. Lai E.K. McCay P.B. J. Clin. Invest. 1988; 82: 476-485Crossref PubMed Scopus (630) Google Scholar), and the injury is limited by antioxidants and free radical scavengers (4Sarvazyan N.A. Askari A. Huang W.H. Life Sci. 1995; 57: 1003-1010Crossref PubMed Scopus (37) Google Scholar). Potential sources of reactive oxygen species generation during ischemia/reperfusion of vascular tissue include superoxide (O·̄2) via neutrophil NADPH oxidase (5McCord J.M. N. Engl. 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In this study, we explored the expression of cyclooxygenase in response to free radical-induced injury of primary cardiomyocytes using H2O2 and doxorubicin, both of which induce cardiac prostaglandin (PG) 1The abbreviations PGprostaglandinsCOXcyclooxygenaseDXdoxorubicinPEGpolyethylene glycolCATcatalaseLDHlactate dehydrogenasePCRpolymerase chain reactionGAPDHglyceraldehyde-3-phosphate dehydrogenaseGC-MSgas chromatography-mass spectrometryERKextracellular signal-regulated kinasesNF-κBnuclear factor transcription factor κBAP-1activator protein-1NBSnewborn calf serumPMAphorbol 12-myristate 13-acetatePBSphosphate-buffered salineHBSSHanks' balanced salt solutionRTreverse transcriptase formation (13Bristow M.R. Kantrowitz N.E. Harrison W.D. Minobe W.A. Sageman W.S. Billingham M.S. J. Cardiovasc. Pharmacol. 1983; 5: 913-919Crossref PubMed Scopus (58) Google Scholar). Cyclooxygenase (COX), the rate-limiting enzyme in prostaglandin synthesis, exists as two isoforms (14Tsujii M. Dubois R.N. 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Cardiac fibrosis has been reported in mice where the COX-2 isoform has been disrupted (18Morham S.G. Lagenbach R. Loftin C.D. Tiano H.F. Vouloumanos N. Jennette J.C. Mahler J.F. Kluckman K.D. Ledford A. Lee C.A. Smithies O. Cell. 1995; 83: 473-482Abstract Full Text PDF PubMed Scopus (1032) Google Scholar), suggesting that COX-2 expression may be protective. prostaglandins cyclooxygenase doxorubicin polyethylene glycol catalase lactate dehydrogenase polymerase chain reaction glyceraldehyde-3-phosphate dehydrogenase gas chromatography-mass spectrometry extracellular signal-regulated kinases nuclear factor transcription factor κB activator protein-1 newborn calf serum phorbol 12-myristate 13-acetate phosphate-buffered saline Hanks' balanced salt solution reverse transcriptase The mitogen-activated protein kinases (MAPKs) are serine/threonine protein kinases and 4 subfamilies have been described. One of the subfamilies, extracellular regulated kinases (ERKs)1/2, is activated by a variety of growth factors, cytokines, and phorbol esters, and regulates cellular proliferation and differentiation (19Davis R.J. J. Biol. Chem. 1993; 268: 14553-14556Abstract Full Text PDF PubMed Google Scholar, 20Boulton T.G. Nye S.H. Robbins D.J. Ip N.Y. Radziejewska E. Morgenbesser S.D. Depinho R.A Paneyotatas N. Cobb M.H. Yancopoulos G.D. Cell. 1991; 65: 663-675Abstract Full Text PDF PubMed Scopus (1500) Google Scholar). In cardiac myocytes activation of ERK1/2 regulates gene expression and is implicated in the development of cellular hypertrophy (21Yamazaki T. Komuro I. Zou Y. S. I. Y. T. R. H. Y. Circulation. 95: PubMed Scopus Google Scholar, J. A. J. Biol. 1994; PubMed Scopus Google Scholar). free radicals induce activation of ERK1/2 and a in cardiac myocytes and cells R. Komuro I. T. Zou Y. S. M. I. Y. Y. J. Clin. Invest. PubMed Scopus Google Scholar, B.S. R.A. S.M. J. Biol. 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The of the role by ERK1/2 activation is unknown. a ERK1/2 activation and COX-2 expression in cardiomyocytes by radicals and a transcription factor decoy to the role of the promoter elements and AP-1 in COX-2 newborn calf serum phorbol 12-myristate 13-acetate hydrogen peroxide doxorubicin catalase superoxide solution and from was from NS-398, and from was from which with the rat was a from from and for and from from for and oligonucleotides for transcription factor decoy from was from ERK1/2 PD098059 and from of neonatal rat cardiomyocytes by a of the by P. A. S. Res. PubMed Scopus Google Scholar). the from to and with and cells in for min at in a cells and into at a of a cardiomyocyte cells in with with hydrogen μg/ml 10 μg/ml 10 100 100 and 100 μg/ml This was with at The cells for addition of the 4 following the cardiomyocytes in with was to and with cells for cardiomyocytes with treatment the was and cells with and COX for min or NS-398 for cells with and of was 50 for 10 min to the of prostaglandin The at for PG 4 following the cardiomyocytes with 50 and or 100 μg/ml was to and with cells for 10 or cardiomyocytes with for of radical scavengers and to cells with The was the cells with and to cells for 10 and 10 these was and at for The cells with and COX for min or NS-398 for cells with and of was 50 for 10 min to the of PG This was at for The cells with and in protein and at for or into and at for In cells with NS-398 or 10 μg/ml with or NS-398, or with 10 μg/ml in the of and for the was and at for the cells with and of was 50 for 10 The was at for PG The cells and into and at for mRNA with or with iloprost, or for with H2O2 or 100 μg/ml and into was also both with the or with or 100 μg/ml and into was The cells into for COX-2 mRNA with 50 PD098059 or for to 50 H2O2 or 100 μg/ml with PD098059 or for 10 or cells to in with 50 PD098059 or for a cardiomyocytes with 50 H2O2 or 100 μg/ml for 10 or by a of cells in cells with and of was 50 for 10 The was at for PG The cells and in protein or into for mRNA with 50 μmH2O2 or 100 μg/ml and 50 or with the and cells with and ERK1/2 activity was using factor decoy by a by J.F. W.L. Dubois R.N. M.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google by the in and 50 The was to and to to The from two and on the rat COX-2 The the to the COX-2 and the to the COX-2 The was A with a in the of the and elements was as a in the decoy was in the at a of cells to 50 H2O2 for 10 or 100 μg/ml for the decoy was to at of the transcription factor in the of with and cells with and of was 50 for 10 The was at for PG The cells and in protein or into for mRNA This was to the expression of COX-1 and COX-2 and of and to at of the gene to dehydrogenase and COX-1 and COX-2 and from was reverse into and this was as for the of at for 10 100 of reverse transcription and of reverse transcriptase and at in a reaction of The reverse transcription reaction was by to for A of the reaction was in the was in a with of and and of The reaction at for at for and COX-2 for at for COX-1 for and at for for and COX-2 on with of the with a of COX-1 and COX-2 with to from In to that the produced at the was rat COX-2 this was from into and by cells with was using a protein to the of to and to at at 4 with of a for COX expression was with a and a the COX-2 expressed by is with COX-2 but not COX-1 P. M. P. Sci. S. A. 1996; PubMed Scopus Google Scholar). for ERK1/2 was with and with a was by in the The release was with a cell injury at where A activity in the activity in with cells and activity in from in which cells with was to the of PG by and cardiomyocytes. of was and with min of the was to with and the with and The was by 50 of a solution in and at The was to the was by 10 of and of in to the of the which was to at The was in and at for The and in of was on a gas to a in the using as the and and The gas was with a and in with an of the was from to at by of the using demonstrated that was the PG in neonatal cardiomyocytes. was by enzyme are expressed as The by on the following a and of cardiomyocytes. that the primary prostaglandin in cardiomyocytes is prostacyclin of PG formation by cardiomyocytes have been reported D.J. J. 1994; PubMed Scopus Google Scholar). of both and was enhanced in response to but of COX-2 activity by NS-398 abolished the increase in and that the increase in these was of COX activity by prevented that its generation was to be generation of in neonatal rat prostaglandins by cardiomyocytes and which This induction was by NS-398, a specific COX-2 or formation was not enhanced by that with that is and was in a The prostaglandins by cardiomyocytes and which This induction was by NS-398, a specific COX-2 or formation was not enhanced by that with that is and was to 50 μmH2O2 for 10 min which not cell that COX-2 expression at not mRNA of COX-1 or the was a corresponding increase in COX-2 whereas the expression of COX-1 not H2O2 also induced at with to by 10 as the expression of COX-2 protein and NS-398 on formation at or at 10 min of but abolished the increase in at that this increase was NS-398 not the expression of COX-2 and was activity not a COX inhibitor, the of at of 10 or 100 μg/ml doxorubicin to cells in a and in of doxorubicin was and cells to for a normal of was of 100 μg/ml doxorubicin to cells for by a not cells to 10 μg/ml doxorubicin induced cell nuclear formation of and in the cell in of 100 μg/ml doxorubicin induced a in COX-2 mRNA 10 min and in COX-1 or mRNA and prevented COX-2 a role for free radicals in COX-2 also caused an increase in This increase in was abolished by NS-398 preventing the expression of that the increase in formation was The increase in was also abolished by with and The release of into cell was as a of cell injury the of cells to 100 μg/ml doxorubicin, was in at 10 was a increase that cell injury was increase in from to 10 The increase in release was by with and increased the of the role of the hydroxyl radical in cell The of 10 μg/ml doxorubicin also induced but at a induced COX-2 at mRNA of COX-1 or also caused an increase in formation A and and prevented COX-2 induction and formation, suggesting a free this a of free radical of doxorubicin may be responsible for the COX-2 is also that doxorubicin at this causes a increase in by the cardiomyocyte P. A. S. Res. PubMed Scopus Google Scholar) which is reported to induce apoptosis and H2O2 J.F. W.L. Dubois R.N. M.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). 10 μg/ml doxorubicin also caused the release of which was prevented by and The COX-2 NS-398 not increase the release of that of The release of was by NS-398 suggesting that a the cells from protect cardiomyocytes from injury, we examined the effects of stable of on release by cells to of H2O2 50 μmH2O2 not a increase in release following the of by H2O2 and cell damage and In an of not release from that the in release was specific for of cardiomyocytes with 50 μmH2O2 or 100 μg/ml doxorubicin increased ERK1/2 activity The increase in ERK1/2 activity was in the of the ERK1/2 PD098059 which also prevented the induction of COX-2 and in response to H2O2 or doxorubicin In the inhibitor, not COX-2 induction and suggesting that COX-2 expression was ERK1/2 of transcription factor and AP-1 on H2O2 and doxorubicin induced COX-2 expression cells 50 100 μg/ml AP-1 AP-1 NF-κB-1 NF-κB-1 NF-κB-2 NF-κB-2 and of COX-1 and COX-2 expression. H2O2 and doxorubicin induced expression of COX-2 COX-1 or The decoy not COX-2 expression 4 and the AP-1 decoy prevented COX-2 expression in response to H2O2 or doxorubicin and A decoy corresponding to the NF-κB-1 on COX-2 and A decoy corresponding to the NF-κB-2 but not COX-2 induction by H2O2 or 10 and corresponding in H2O2 or doxorubicin induced formation The increase was abolished by the AP-1 decoy and by the NF-κB-2 decoy with oligonucleotides at corresponding to COX-2 promoter elements to as for transcription that may be and the elements responsible for the induction of COX-2. A decoy corresponding to the promoter prevented COX-2 expression in response to H2O2 or doxorubicin decoy corresponding to the NF-κB-2 also but not the induction of whereas an decoy corresponding to the NF-κB-1 COX-2 promoter has been in human cardiomyocytes in of and from with dilated cardiomyopathy, whereas COX-2 was in normal (17Wong S.C.Y. Fukuchi M. Melynk P. Rodger I. Giaid A. 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