THE MEKK-JNK PATHWAY IS STIMULATED BY ALPHA(1)-ADRENERGIC RECEPTOR AND RAS ACTIVATION AND IS ASSOCIATED WITH IN-VITRO AND IN-VIVO CARDIAC-HYPERTROPHY

In neonatal rat ventricular myocytes, stimulation of the alpha(1)-adre nergic receptor (alpha(1)-AdrR) activates a program of genetic and mor phological changes characterized by transcriptional activation of the atrial natriuretic factor (ANF) gene and enlargement (hypertrophy) of the cells. The low molecular weight GTPase Ras has been established as an important regulator of hypertrophy both in vitro and in vivo. Ras activates a kinase cascade involving Raf, the mitogen-activated protei n kinase kinase (MEK), and the extracellular signal-regulated protein kinase (ERK), However, the extent of involvement of this pathway in re gulating hypertrophic responses is controversial. We demonstrate here that both alpha(1)-AdrR stimulation and Ras can also activate the c-Ju n NH2-terminal kinase (JNK) in cardiomyocytes. The alpha(1)-AdrR effec t on JNK occurs through a pathway requiring Ras and MEK kinase (MEKK). A constitutively activated mutant of MEKK that preferentially activat es JNK, stimulates ANF reporter gene expression, while a dominant nega tive MEKK mutant inhibits ANF expression induced by PE. Furthermore, J NK activity is increased in the ventricles of mice overexpressing onco genic Ras, whereas ERK activity is not, These results suggest that the alpha(1)-AdrR mediates ANF gene expression through a Ras-MEKK-JNK pat hway and that activation of this pathway is associated with in vitro a nd in vivo hypertrophy.