Transcription activator protein 1 (AP-1) mediates NO-induced apoptosis of adult cardiomyocytes

Release of nitric oxide (NO) during inflammation can induce apoptosis in th e heart. Here we analyzed the involvement of members of the mitogen-activat ed protein kinase (MAPK) family and their downstream target, the transcript ion factor AP-1, in induction of apoptosis by NO in isolated adult cardiomy ocytes of rat. The NO-donor (+/-)- S-nitroso-N-acetylpenicillamine (100 muM SNAP)- induced apoptosis in 10.5 +/- 0.7% of cardiomyocytes and activated the transcription activator protein AP-1 by 333.6 +/- 122.3%. Intracellular scavenging of AP-1 with decoyoligonucleotides blocked NO-induced apoptosis to control levels (3.8 +/- 0.5% apoptotic cells). Activation of AP-1 with a c-Jun amino-terminal kinase (JNK) activator (Ro318220, 10 muM) provoked a poptosis in 18.7 +/- 1.2% cardiomyocytes, which was again blocked by intrac ellular scavenging of AP-1. NO activated JNK by 87.0 +/- 27.3% and extracel lular signal-regulated kinase (ERK) by 35 +/- 3%. Inhibition of ERK by the mitogen-activated protein kinase kinase (MEK1) inhibitor PD98059 (10 muM) a bolished AP-1 activation and apoptosis induction with SNAP. Evidence that p 38 MAPK plays a role in NO-induced apoptosis was not found. These results c learly demonstrate the involvement of the transcription factor AP-1 in NO-i nduced apoptosis in cardiomyocytes. The activation of AP-1 is mediated by t he two MAP kinases JNK and ERK.