OPPOSING EFFECTS OF JUN KINASE AND P38 MITOGEN-ACTIVATED PROTEIN-KINASES ON CARDIOMYOCYTE HYPERTROPHY

c-Jun N-terminal protein kinase (JNK) and p38, two distinct members of the mitogen-activated protein (MAP) kinase family, regulate gene expr ession in response to various extracellular stimuli, yet their physiol ogical functions are not completely understood. In this report we show that JNK and p38 exerted opposing effects on the development of myocy te hypertrophy, which is an adaptive physiological process characteriz ed by expression of embryonic genes and unique morphological changes. In rat neonatal ventricular myocytes, both JNK and p38 were stimulated by hypertrophic agonists like endothelin-1, phenylephrine, and leukem ia inhibitory factor. Expression of MAP kinase kinase 6b (EE), a const itutive activator of p38, stimulated the expression of atrial natriure tic factor (ANF), which is a genetic marker of in vivo cardiac hypertr ophy. Activation of p38 was required for ANF expression induced by the hypertrophic agonists. Furthermore, a specific p38 inhibitor, SB20219 0, significantly changed hypertrophic morphology induced by the agonis ts. Surprisingly, activation of JNK led to inhibition of ANF expressio n induced by MEK kinase 1 (MEKK1) and the hypertrophic agonists. MEKK1 -induced ANF expression was also negatively regulated by expression of c-Jun. Our results demonstrate that p38 mediates, but JNK suppresses, the development of myocyte hypertrophy.