Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: Comparison with acute mechanical stretch

Activation of members of the mitogen-activated protein (MAP) kinase family and their downstream effectors has been proposed to play a key role in the pathogenesis of cell survival, ischaemic preconditioning, cardiac hypertrop hy and heart failure. This study investigated the responses of Src kinase a nd multiple MAP kinases during the transition from compensated pressure-ove rload hypertrophy to decompensated congestive heart failure. Extracellular signal-regulated protein kinase (ERK) 1/2, p3g, and Src were activated by c hronic pressure-overload and their activity was sustained for 8 weeks after aortic banding. In contrast, while p90 ribosomal S6 kinase (90RSK) and big MAP kinase 1 (BMK1) were activated in compensated hypertrophy, their activ ities were significantly decreased in hearts with heart failure. No changes were found in C-Jun NH2 terminal kinase (JNK) activity after aortic bandin g. These data suggest that differential activation of MAP kinase family mem bers may contribute to the transition from compensated to decompensated hyp ertrophy. We also examined acute effects of mechanical stretch on the activ ation of these kinases in normal and hypertrophied hearts. In the isolated coronary-perfused heart. a balloon in the left ventricle was inflated to ac hieve minimum end-diastolic pressure of 25 mmHg for 10-20min. In normal gui nea pig hearts. stretch activated ERK1/2, p90RSK, p38, Src. and BMK1 but no t JNK. However in hypertrophied hearts. further activation of these kinases was not observed by acute mechanical stretch. Mechanical stretch-induced a ctivation of ERK1/2 and p38 kinase in normal hearts was attenuated signific antly by a protein kinase C inhibitor, chelerythrine. We demonstrate that E RK1/2, p90RSK, p38, Src, and BMK1 are activated by chronic pressure-overloa d and by acute mechanical stretch. These data suggest that Src. BMK1 and p9 0RSK play a role as novel signal transduction pathways leading to cardiac h ypertrophy. In addition, the differential inhibition of p90RSK and BMK1 in hearts with congestive heart failure suggests the specific role of these tw o kinases to maintain cardiac function under chronic pressure-overload. (C) 2001 Academic Press.