VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) ACTIVATES RAF-1, MITOGEN-ACTIVATED PROTEIN (MAP) KINASES, AND S6 KINASE (P90(RSK)) IN CULTURED RAT CARDIAC MYOCYTES

Rapid activation of intracellular signaling cascades is induced in car diac myocytes in response to various external stresses. Vascular endot helial growth factor (VEGF) is a potent angiogenic mitogen secreted fr om tumor cells and cells exposed to hypoxia such as ischemic myocardia l cells. To clarify the mechanisms of how cardiac myocytes respond and adapt to ischemic stresses, we investigated the intracellular signali ng cascades in cultured rat cardiac myocytes in response to VEGF. We s how that rapid activation of mitogen-activated protein kinase kinase k inase (MAPKKK) of Raf-l, MAP kinases, and S6 kinase (p90(rsk)) was ind uced in cardiac myocytes in response to VEGF. This activation of MAP k inases was also induced in fibroblasts. VEGF also caused phosphorylati on of the activating transcription factor 2. Furthermore, VEGF strongl y induced a transcription factor jun-B mRNA in cardiac myocytes. These results indicated that MAP kinase pathway is rapidly activated in car diac myocytes and fibroblasts in response to VEGF. It is strongly sugg ested that cardiac myocytes are one of the targets of VEGF and that ca rdiac response to ischemic stresses may be at least partly mediated by VEGF. (C) 1998 Wiley-Liss, Inc.