CARDIAC-HYPERTROPHY INDUCED BY MITOGEN-ACTIVATED PROTEIN-KINASE KINASE-7, A SPECIFIC ACTIVATOR FOR C-JUN NH2-TERMINAL KINASE IN VENTRICULARMUSCLE-CELLS

Activation of stress-activated protein kinases, including the p38 and the c-Jun NH2-terminal kinases (JNK), have been associated with the on set of cardiac hypertrophy and cell death in response to hemodynamic o verload and ischemia/reperfusion injury. Upon infection of cultured ne onatal rat cardiac myocytes with recombinant adenoviral vectors expres sing a wild type and a constitutively active mutant of MKK7 (or JNKK2) , JNK was specifically activated without affecting other mitogen-activ ated protein kinases, including extracellular signal-regulated protein kinases and p38. Specific activation of the JNK pathway in cardiac my ocytes induced characteristic features of hypertrophy, including an in crease in cell size, elevated expression of atrial natriuretic factor, and induction of sarcomere organization. In contrast, co-activation o f both JNK (by MKK7) and p38 (by MKK3 or MKK6) in cardiomyocytes led t o an induction of cytopathic responses and suppression of hypertrophic responses. These data provide the first direct evidence that activati on of JNK alone is sufficient to induce characteristic features of car diac hypertrophy, thereby supporting an active role for the JNK pathwa y in the development of cardiac hypertrophy, The cytopathic response, as a result of co activation of both JNK and p38, may contribute to th e loss of contractile function and viability of cardiomyocytes followi ng hemodynamic overload and cardiac ischemia/reperfusion injury.