Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH2-terminal kinases

Cardiac hypertrophy often presages the development of heart failure. Numero us cytosolic signaling pathways have been implicated in the hypertrophic re sponse in cardiomyocytes in culture, but their roles in the hypertrophic re sponse to physiologically relevant stimuli in vivo is unclear. We previousl y reported that adenovirus-mediated gene transfer of SEK-1(KR), a dominant inhibitory mutant of the immediate upstream activator of the stress-activat ed protein kinases (SAPKs), abrogates the hypertrophic response of neonatal rat cardiomyocytes to endothelin-l in culture. We now report that gene tra nsfer of SEK-1(KR) to the adult rat heart blocks SAPK activation by pressur e overload, demonstrating that the activity of cytosolic signaling pathways can be inhibited by gene transfer of loss-of-function mutants in vivo. Fur thermore, gene transfer of SEK-1(KR) inhibited pressure overload-induced ca rdiac hypertrophy, as determined by echocardiography and several postmortem measures including left ventricular (LV) wall thickness, the ratio of LV w eight to body weight, cardiomyocyte diameter, and inhibition of atrial natr iuretic factor expression. Our data suggest that the SAPKs are critical reg ulators of cardiac hypertrophy in vivo, and therefore may serve as novel dr ug targets in the treatment of hypertrophy and heart failure.