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Title

The PGE2-Stat3 interaction in doxorubicin-induced myocardial apoptosis

Authors
Somers, Sarin
Gerber-Wicht, Christine
Opie, Lionel H.
Lecour, Sandrine
Published in Cardiovascular Research. 2008, vol. 80, no. 1, p. 69-77
Abstract AIMS: Both cyclooxygenase-2 (COX-2) and the transcription factor signal transducer and activator of transcription 3 (Stat3) are involved in adaptive growth and survival of cardiomyocytes. In ventricular cardiomyocytes, prostaglandin E(2) (PGE(2)), a major COX-2 product, leads to adaptive growth via Stat3 activation, but whether this transcription factor acts as a signalling molecule in PGE(2)-induced cell survival is unknown. Therefore, the purpose of this study was to determine whether PGE(2) counteracts cardiac apoptosis induced by doxorubicin (DOX), and if so, whether Stat3 plays a critical role in this cardioprotective effect. METHODS AND RESULTS: Neonatal rat ventricular cardiomyocytes were incubated with DOX (0.5 microM) and/or PGE(2) (1 microM). Apoptosis was assessed by determining caspase3 activation and apoptotic DNA fragmentation. The role of Stat3 was evaluated in vitro and in vivo by transfecting cardiomyocytes with siRNA targeting rat Stat3 and by using cardiomyocyte-restricted Stat3 knockout (Stat3 KO) mice, respectively. Incubation of ventricular cardiomyocytes with PGE(2) led to a time-dependent decrease in the DOX-induced caspase3 activation, reaching a maximal inhibition of 70 +/- 5% after 4 h. Similarly, PGE(2) inhibited DOX-induced DNA fragmentation by 58 +/- 5% after 24 h. This antiapoptotic action of PGE(2) was strongly reduced by the ERK1/2 inhibitor, U0126, whereas the p38 MAP kinase inhibitor, SB203580, had no effect. Depleting Stat3 expression by 50-60% in isolated ventricular cardiomyocytes markedly reduced the protective effect of PGE(2) on DOX-induced caspase3 activation and DNA fragmentation. Likewise, the stable PGE(2) analogue, 16,16-dimethyl-PGE(2), was unable to counteract cardiac apoptosis induced by DOX in Stat3 KO mice. CONCLUSION: Our results demonstrate that PGE(2) prevents myocardial apoptosis induced by DOX. This protection requires the activation of the prosurvival pathways of Stat3 and ERK1/2.
Keywords AnimalsAntibiotics, Antineoplastic/pharmacologyApoptosis/drug effectsCell SurvivalCells, CulturedDinoprostone/metabolismDoxorubicin/pharmacologyExtracellular Signal-Regulated MAP Kinases/metabolismMiceMice, KnockoutMyocytes, Cardiac/metabolismRatsRats, WistarSTAT3 Transcription Factor/metabolism
Stable URL http://archive-ouverte.unige.ch/unige:1148
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PMID: 18567640
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Deposited on : 2009-03-16

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