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  • Title: Transcription activator protein 1 (AP-1) mediates NO-induced apoptosis of adult cardiomyocytes.
    Author: Taimor G, Rakow A, Piper HM.
    Journal: FASEB J; 2001 Nov; 15(13):2518-20. PubMed ID: 11641266.
    Abstract:
    Release of nitric oxide (NO) during inflammation can induce apoptosis in the heart. Here we analyzed the involvement of members of the mitogen-activated protein kinase (MAPK) family and their downstream target, the transcription factor AP-1, in induction of apoptosis by NO in isolated adult cardiomyocytes of rat. The NO-donor (+/-)-S-nitroso-N-acetylpenicillamine (100 microM 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 decoy-oligonucleotides 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 microM) provoked apoptosis in 18.7 +/- 1.2% cardiomyocytes, which was again blocked by intracellular scavenging of AP-1. NO activated JNK by 87.0 +/- 27.3% and extracellular signal-regulated kinase (ERK) by 35 +/- 3%. Inhibition of ERK by the mitogen-activated protein kinase kinase (MEK1) inhibitor PD98059 (10 microM) abolished AP-1 activation and apoptosis induction with SNAP. Evidence that p38 MAPK plays a role in NO-induced apoptosis was not found. These results clearly demonstrate the involvement of the transcription factor AP-1 in NO-induced apoptosis in cardiomyocytes. The activation of AP-1 is mediated by the two MAP kinases JNK and ERK.
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