PMID- 10747006
OWN - NLM
STAT- MEDLINE
DCOM- 20000419
LR  - 20220410
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 86
IP  - 6
DP  - 2000 Mar 31
TI  - Inhibition of extracellular signal-regulated kinase enhances 
      Ischemia/Reoxygenation-induced apoptosis in cultured cardiac myocytes and 
      exaggerates reperfusion injury in isolated perfused heart.
PG  - 692-9
AB  - Three major mammalian mitogen-activated protein kinases, extracellular 
      signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal protein kinase 
      (JNK), have been identified in the cardiomyocyte, but their respective roles in 
      the heart are not well understood. The present study explored their functions and 
      cross talk in ischemia/reoxygenation (I/R)-induced cardiac apoptosis. Exposing 
      rat neonatal cardiomyocytes to ischemia resulted in a rapid and transient 
      activation of ERK, p38, and JNK. On reoxygenation, further activation of all 3 
      mitogen-activated protein kinases was noted; peak activities increased (fold) by 
      5.5, 5.2, and 6.2, respectively. Visual inspection of myocytes exposed to I/R 
      identified 18.6% of the cells as showing morphological features of apoptosis, 
      which was further confirmed by DNA ladder and terminal deoxyribonucleotide 
      transferase-mediated dUTP nick end labeling (TUNEL). Myocytes treated with 
      PD98059, a MAPK/ERK kinase (MEK1/MEK2) inhibitor, displayed a suppression of 
      I/R-induced ERK activation, whereas p38 and JNK activities were increased by 
      70.3% and 55.0%, respectively. In addition, the number of apoptotic cells was 
      increased to 33.4%. With pretreatment of cells with SB242719, a selective p38 
      inhibitor, or SB203580, a p38 and JNK2 inhibitor, I/R+PD98059-induced apoptotic 
      cells were reduced by 42.8% and 63.3%, respectively. Hearts isolated from rats 
      treated with PD98059 and subjected to global ischemia (30 minutes)/reoxygenation 
      (1 hour) showed a diminished functional recovery compared with the vehicle group. 
      Coadministration of SB203580 attenuated the detrimental effects of PD98059 and 
      significantly improved cardiac functional recovery. The data taken together 
      suggest that ERK plays a protective role, whereas p38 and JNK mediate apoptosis 
      in cardiomyocytes subjected to I/R, and the dynamic balance of their activities 
      is critical in determining cardiomyocyte fate subsequent to reperfusional injury.
FAU - Yue, T L
AU  - Yue TL
AD  - Departments of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, 
      King of Prussia, PA 19406, USA.
FAU - Wang, C
AU  - Wang C
FAU - Gu, J L
AU  - Gu JL
FAU - Ma, X L
AU  - Ma XL
FAU - Kumar, S
AU  - Kumar S
FAU - Lee, J C
AU  - Lee JC
FAU - Feuerstein, G Z
AU  - Feuerstein GZ
FAU - Thomas, H
AU  - Thomas H
FAU - Maleeff, B
AU  - Maleeff B
FAU - Ohlstein, E H
AU  - Ohlstein EH
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Flavonoids)
RN  - 0 (Imidazoles)
RN  - 0 (Pyridines)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - OU13V1EYWQ (SB 203580)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
SB  - IM
CIN - Circ Res. 2000 Mar 31;86(6):607-9. PMID: 10746992
MH  - Animals
MH  - Animals, Newborn
MH  - Apoptosis/drug effects/*physiology
MH  - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
MH  - Cells, Cultured
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - Flavonoids/pharmacology
MH  - Heart/*physiopathology
MH  - Imidazoles/pharmacology
MH  - In Vitro Techniques
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors/metabolism
MH  - Myocardial Ischemia/pathology/*physiopathology
MH  - Myocardial Reperfusion Injury/pathology/*physiopathology
MH  - Myocardium/*enzymology/pathology
MH  - Pyridines/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recovery of Function/drug effects
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 2000/04/04 09:00
MHDA- 2000/04/25 09:00
CRDT- 2000/04/04 09:00
PHST- 2000/04/04 09:00 [pubmed]
PHST- 2000/04/25 09:00 [medline]
PHST- 2000/04/04 09:00 [entrez]
AID - 10.1161/01.res.86.6.692 [doi]
PST - ppublish
SO  - Circ Res. 2000 Mar 31;86(6):692-9. doi: 10.1161/01.res.86.6.692.