Activators of PPARgamma antagonize protection of cardiac myocytes by endothelin-1.
Endothelin-1 (ET-1) is a potent survival factor against myocardial cell apoptosis. This anti-apoptotic effect of ET-1 is mediated in part through calcineurin/NFATc-dependent induction of bcl-2 expression. Since it has been reported that peroxisome proliferator-activated receptor-gamma (PPARgamma) interacts with NFATc, we investigated the effects of PPARgamma ligands on anti-apoptotic effects of ET-1 in cardiac myocytes. In primary cardiac myocytes from neonatal rats, administration of PPARgamma activators (15-deoxy-delta12,14-prostaglandin J2 and troglitazone) attenuated the anti-apoptotic effects of ET-1. These activators abolished the ET-1-stimulated increase in bcl-2 expression and in binding of cardiac NFATc to the bcl-2 NFAT site. These findings demonstrate that activators of PPARgamma perturb the anti-apoptotic effects of ET-1 in cardiac myocytes and that this perturbation is, in part, based on functional transcriptional cross-talk between NFATc and PPARgamma.
Ehara
Natsuhiko
N
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Hasegawa
Koji
K
Ono
Koh
K
Kawamura
Teruhisa
T
Iwai-Kanai
Eri
E
Morimoto
Tatsuya
T
Akao
Masaharu
M
Adachi
Souichi
S
Kita
Toru
T
D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002316:Cardiotonic Agents; D002839:Chromans; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D004247:DNA; D000077288:Troglitazone; D015230:Prostaglandin D2