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.
MeSH terms
-
Animals
-
Apoptosis / drug effects*
-
Apoptosis / physiology
-
Cells, Cultured
-
Enzyme Activation / drug effects
-
Enzyme Inhibitors / pharmacology
-
Flavonoids / pharmacology
-
Heart Ventricles / cytology
-
Heart Ventricles / drug effects*
-
Heart Ventricles / metabolism
-
Imidazoles / pharmacology
-
Indoles / pharmacology
-
JNK Mitogen-Activated Protein Kinases*
-
MAP Kinase Kinase 4
-
Mitogen-Activated Protein Kinase Kinases / metabolism
-
Mitogen-Activated Protein Kinases / antagonists & inhibitors
-
Mitogen-Activated Protein Kinases / metabolism
-
Nitric Oxide / physiology*
-
Nitric Oxide Donors / pharmacology*
-
Oligonucleotides / genetics
-
Oligonucleotides / metabolism
-
Penicillamine / analogs & derivatives*
-
Penicillamine / pharmacology*
-
Protein Binding / drug effects
-
Pyridines / pharmacology
-
Rats
-
Transcription Factor AP-1 / drug effects*
-
Transcription Factor AP-1 / metabolism
-
p38 Mitogen-Activated Protein Kinases
Substances
-
Enzyme Inhibitors
-
Flavonoids
-
Imidazoles
-
Indoles
-
Nitric Oxide Donors
-
Oligonucleotides
-
Pyridines
-
S-nitro-N-acetylpenicillamine
-
Transcription Factor AP-1
-
Nitric Oxide
-
JNK Mitogen-Activated Protein Kinases
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase 4
-
Mitogen-Activated Protein Kinase Kinases
-
Penicillamine
-
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
-
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
-
Ro 31-8220