ROLE OF THE STRESS-ACTIVATED PROTEIN-KINASES IN ENDOTHELIN-INDUCED CARDIOMYOCYTE HYPERTROPHY

The signal transduction pathways governing the hypertrophic response o f cardiomyocytes are not well defined. Constitutive activation of the stress-activated protein kinase (SAPK) family of mitogen-activated pro tein (MAP) kinases or another stress-response MAP kinase, p38, by over expression of activated mutants of various components of the pathways is sufficient to induce a hypertrophic response in cardiomyocytes, but it is not clear what role these pathways play in the response to phys iologically relevant hypertrophic stimuli. To determine the role of th e SAPKs in the hypertrophic response, we used adenovirus-mediated gene transfer of SAPK/ERK kinase-1 (KR) [SEK-1(KR)], a dominant inhibitory mutant of SEK-1, the immediate upstream activator of the SAPKs, to bl ock signal transmission down the SAPK pathway in response to the poten t hypertrophic agent, endothelin-1 (ET-1). SEK-1(KR) completely inhibi ted ET-1-induced SAPK activation without affecting activation of the o ther MAP kinases implicated in the hypertrophic response, p38 and extr acellular signal-regulated protein kinases (ERK)-1/ERK-2, Expression o f SEK-1(KR) markedly inhibited the ET-1-induced increase in protein sy nthesis. In contrast, the MAPK/ERK kinase inhibitor, PD98059, which bl ocks ERK activation, and the p38 inhibitor, SB203580, had no effect on ET-1-induced protein synthesis. ET-1 also induced a significant incre ase in atrial natriuretic factor mRNA expression as well as in the per centage of cells with highly organized sarcomeres, responses which wer e also blocked by expression of SEK-1(KR), In summary, inhibiting acti vation of the SAPK pathway abrogated the hypertrophic response to ET-1 , These data are the first demonstration that the SAPKs are necessary for the development of agonist-induced cardiomyocyte hypertrophy, and suggest that in response to ET-1, they transduce critical signals gove rning the hypertrophic response.