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 microM H2O2 for 10 min or doxorubicin at 10 and 100 micrograms/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-kappaB-2 but not the NF-kappaB-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.
Adderley
S R
SR
Centre for Cardiovascular Science, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland.
Fitzgerald
D J
DJ
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004247:DNA; D004317:Doxorubicin / Q000494:pharmacology; D004790:Enzyme Induction; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016285:Iloprost / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000378:metabolism