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-kappa B (NF-kappa B) DNA binding activities, all of which seem to be important in a signal transduction cascade upstre am of the increased level of mRNA expression observed after myocardial infarction. Methods: Myocardial infarction was produced in Wistar rat s. 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-kapp a B binding was determined using an electrophoretic mobility shift ass ay. Levels of transforming growth factor beta 1(TGF-beta 1) and collag en I and III mRNAs were analyzed by Northern blot hybridization. Resul ts: p42 Extracellular signal-regulated kinase (ERK), p44ERK and p38MAP K activities increased 5.2-fold, 4.3-fold and 1.9-fold (P < 0.01), res pectively, at 5 min after coronary artery ligation but returned to nor mal levels by 30 min. p55 c-Jun NH2-terminal kinase (JNK) and p46JNK a ctivities 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-kappa B binding activities increased 8.7-fold and 7.1-fold (P < 0.01), respectively, at 3 days but returned to normal levels by 7 da ys 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 a nd 12.0-fold (P < 0.01), respectively, at 1 week after myocardial infa rction. Conclusions: Myocardial ischemia increased MAPK activities, wh ich were followed by enhancement of AP-1 and NF-kappa B DNA binding ac tivity in areas of myocardial infarction in rats. These signal transdu ction mechanisms may contribute to the myocardial ischemia and injury associated with myocardial infarction by causing an increased expressi on of TGF-beta 1 mRNA, collagen I and III in the area. (C) 1998 Elsevi er Science B.V.