Cytoprotection by Jun kinase during nitric oxide-induced cardiac myocyte apoptosis.
Nitric oxide (NO) induces apoptosis in cardiac myocytes through an oxidant-sensitive mechanism. However, additional factors appear to modulate the exact timing and rate of NO-dependent apoptosis. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated kinase [ERK] 1/2, c-Jun N-terminal kinase [JNK] 1/2, and p38MAPK) in NO-mediated apoptotic signaling. The NO donor S:-nitrosoglutathione (GSNO) induced caspase-dependent apoptosis in neonatal rat cardiac myocytes, preceded by a rapid (<10-minute) and significant (approximately 50-fold) activation of JNK1/2. Activation of JNK was cGMP dependent and was inversely related to NO concentration; it was maximal at the lowest dose of GSNO (10 micromol/L) and negligible at 1 mmol/L. NO slightly increased ERK1/2 beginning at 2 hours but did not affect p38MAPK activity. Inhibitors of ERK and p38MAPK activation did not affect cell death rates. In contrast, expression of dominant-negative JNK1 or MKK4 mutants significantly increased NO-induced apoptosis at 5 hours (56.77% and 57.37%, respectively, versus control, 40.5%), whereas MEKK1, an upstream activator of JNK, sharply reduced apoptosis in a JNK-dependent manner. Adenovirus-mediated expression of dominant-negative JNK1 both eliminated the rapid activation of JNK by NO and accelerated NO-mediated apoptosis by approximately 2 hours. These data indicate that NO activates JNK as part of a cytoprotective response, concurrent with initiation of apoptotic signaling. Early, transient activation of JNK serves both to delay and to reduce the total extent of apoptosis in cardiac myocytes.
Andreka
P
P
Department of Molecular and Cellular Pharmacology, University of Miami, FL, USA.
Zang
J
J
Dougherty
C
C
Slepak
T I
TI
Webster
K A
KA
Bishopric
N H
NH
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004274:DNA, Recombinant; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology; D009569:Nitric Oxide / Q000502:physiology*; D009603:Nitroso Compounds / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D026422:S-Nitrosoglutathione; D014162:Transfection; D000099190:MAP-Kinase-Activated Kinase 2
D000590:Amino Acid Chloromethyl Ketones; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases; D006152:Cyclic GMP; D015853:Cysteine Proteinase Inhibitors; D004274:DNA, Recombinant; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005978:Glutathione; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009569:Nitric Oxide; D009603:Nitroso Compounds; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D026422:S-Nitrosoglutathione; D000099190:MAP-Kinase-Activated Kinase 2; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C016276:8-bromocyclic GMP; C505410:Casp3 protein, rat; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one