Activation of cardiac c-Jun NH2-terminal kinases and p38-mitogen-activatedprotein kinases with abrupt changes in hemodynamic load

The role of mitogen-activated protein kinase (MAPK) pathways as signal tran sduction intermediates of hemodynamic stress leading to cardiac hypertrophy in the adult heart is not fully established. In a rat model of pressure-ov erload hypertrophy, we examined whether activation of MAPK pathways, namely , the extracellular signal-regulated protein kinase (ERK), c-Jun NH2-termin al kinase (JNK), and the p38-MAPK pathways, occurs during rapid changes in hemodynamic load in vivo. A slight activation of ERK2 and marked increases in JNK1 and p38-MAPK activities were observed 30 minutes after aortic bandi ng. The increase in p38-MAPK activity was accompanied by an increase in the phosphorylation of the p38 substrate MAPK-activated protein kinases 2 and 3. Activation of these kinases was coincident with an increase in phosphory lation of c-Jun and activating transcription factor-2 (ATF-2) and enhanced DNA binding of activator protein-1 factors. Thus, hemodynamic stress of the adult rat heart in vivo results in rapid activation of several parallel MA PK kinase cascades, particularly stress-activated MAPK and p38-MAPK and the ir target transcription factors c-Jun and ATF-2.