The PGE2-Stat3 interaction in doxorubicin-induced myocardial apoptosis.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Division of Endocrinology, Diabetology and Nutrition, University Hospital, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. miguel.frias@medecine.unige.ch
Miguel A
MA
Frias
Sarin
S
Somers
Christine
C
Gerber-Wicht
Lionel H
LH
Opie
Sandrine
S
Lecour
Ursula
U
Lang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone