Vascular endothelial growth factor (VEGF) activates Raf-1, mitogen-activated protein (MAP) kinases, and S6 kinase (p90rsk) in cultured rat cardiac myocytes.
Rapid activation of intracellular signaling cascades is induced in cardiac myocytes in response to various external stresses. Vascular endothelial growth factor (VEGF) is a potent angiogenic mitogen secreted from tumor cells and cells exposed to hypoxia such as ischemic myocardial cells. To clarify the mechanisms of how cardiac myocytes respond and adapt to ischemic stresses, we investigated the intracellular signaling cascades in cultured rat cardiac myocytes in response to VEGF. We show that rapid activation of mitogen-activated protein kinase kinase kinase (MAPKKK) of Raf-1, MAP kinases, and S6 kinase (p90rsk) was induced in cardiac myocytes in response to VEGF. This activation of MAP kinases was also induced in fibroblasts. VEGF also caused phosphorylation of the activating transcription factor 2. Furthermore, VEGF strongly induced a transcription factor jun-B mRNA in cardiac myocytes. These results indicated that MAP kinase pathway is rapidly activated in cardiac myocytes and fibroblasts in response to VEGF. It is strongly suggested that cardiac myocytes are one of the targets of VEGF and that cardiac response to ischemic stresses may be at least partly mediated by VEGF.
Seko
Y
Y
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Takahashi
N
N
Tobe
K
K
Ueki
K
K
Kadowaki
T
T
Yazaki
Y
Y
D051698:Activating Transcription Factor 2; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology; D005786:Gene Expression Regulation / Q000502:physiology; D008222:Lymphokines / Q000494:pharmacology*; D004676:Myelin Basic Protein / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D016228:Endothelial Growth Factors; D008222:Lymphokines; D004676:Myelin Basic Protein; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017346:Protein Serine-Threonine Kinases