Activation of mitogen-activated protein kinases and activator protein-1 in myocardial infarction in rats.
OBJECTIVE
The purpose of this study was to examine the activation of mitogen-activated protein kinases (MAPK) plus activator protein-1 (AP-1) and nuclear factor-kB (NF-kB) DNA binding activities, all of which seem to be important in a signal transduction cascade upstream of the increased level of mRNA expression observed after myocardial infarction.


METHODS
Myocardial infarction was produced in Wistar rats. The activities of MAPKs in the ischemic region were measured using an in-gel kinase method or an in vitro kinase method. AP-1 and NF-kB binding was determined using an electrophoretic mobility shift assay. Levels of transforming growth factor beta-1(TGF-beta-1) and collagen I and III mRNAs were analyzed by Northern blot hybridization.


RESULTS
p42 Extracellular signal-regulated kinase (ERK), p44ERK and p38MAPK activities increased 5.2-fold, 4.3-fold and 1.9-fold (P < 0.01), respectively, at 5 min after coronary artery ligation but returned to normal levels by 30 min. p55c-Jun NH2-terminal kinase (JNK) and p46JNK activities increased 4.0-fold and 3.2-fold (P < 0.01), respectively, at 15 min and returned to normal levels by 24 h after ligation. AP-1 DNA and NF-kB binding activities increased 8.7-fold and 7.1-fold (P < 0.01), respectively, at 3 days but returned to normal levels by 7 days after ligation. Interestingly, analyses of the levels of TGF-beta-1, collagen I and III mRNAs revealed increases of 6.3-fold, 15.2-fold and 12.0-fold (P < 0.01), respectively, at 1 week after myocardial infarction.


CONCLUSIONS
Myocardial ischemia increased MAPK activities, which were followed by enhancement of AP-1 and NF-kB DNA binding activity in areas of myocardial infarction in rats. These signal transduction mechanisms may contribute to the myocardial ischemia and injury associated with myocardial infarction by causing an increased expression of TGF-beta-1 mRNA, collagen I and III in the area.
Shimizu
N
N
First Department of Internal Medicine, Osaka City University Medical School, Japan.
Yoshiyama
M
M
Omura
T
T
Hanatani
A
A
Kim
S
S
Takeuchi
K
K
Iwao
H
H
Yoshikawa
J
J
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics
D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D003094:Collagen; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases