CARDIAC-MUSCLE CELL HYPERTROPHY AND APOPTOSIS INDUCED BY DISTINCT MEMBERS OF THE P38 MITOGEN-ACTIVATED PROTEIN-KINASE FAMILY

p38 mitogen-activated protein (MAP) kinase activities were significant ly increased in mouse hearts after chronic transverse aortic constrict ion, coincident with the onset of ventricular hypertrophy. Infection o f cardiomyocytes with adenoviral vectors expressing up-stream activato rs for the p38 kinases, activated mutants of MAP kinase kinase 3b(E) ( MKK3bE) and MAP kinase kinase 6b(E) (MKK6bE), elicited characteristic hypertrophic responses, including an increase in cell size, enhanced s arcomeric organization, and elevated atrial natriuretic factor express ion. Overexpression of the activated MKK3bE in cardiomyocytes also led to an increase in apoptosis. The hypertrophic response was enhanced b y co-infection of an adenoviral vector expressing wild type p38 beta, and was suppressed by the p38 beta dominant negative mutant. In contra st, the MKK3bE-induced cell death was increased by co-infection of an adenovirus expressing wild type p38 alpha, and was suppressed by the d ominant negative p38 alpha mutant. This provides the first evidence in any cell system for divergent physiological functions for different m embers of the p38 MAP kinase family. The direct involvement of p38 pat hways in cardiac hypertrophy and apoptosis suggests a significant role for p38 signaling in the pathophysiology of heart failure.