Mechanical stretch activates the stress-activated protein kinases in cardiac myocytes.
We have recently shown that mechanical stress activates a phosphorylation cascade of protein kinases including Raf-1 and the extracellular signal-regulated kinases (ERKs) in cultured cardiac myocytes partially through the enhanced secretion of angiotensin II. Osmotic stress in budding yeast has been shown to activate similar signaling molecules including Hog-1, a distant relative of the ERK family. In the present study, we examined whether mechanical stretch of cardiac myocytes activates the stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinase, the mammalian homologs of yeast Hog-1 that regulate gene expression through activation of the transcription factor, AP-1. When cardiac myocytes of neonatal rats cultured on a deformable silicone dish were stretched, activity of SAPKs was increased from 10 min, peaked at 30 min, and gradually decreased thereafter. The increase in activity of SAPKs was proportional to the stretch. Unlike ERKs, the activation of SAPKs by stretching cardiac myocytes was not dependent on the secreted angiotensin II. The chelation of extracellular Ca2+ or down-regulation of protein kinase C did not attenuate activation of SAPKs by stretch. Transfection experiments using an AP-1 binding site-containing reporter gene revealed that stretch increases AP-1 activity in cardiac myocytes. In conclusion, like osmotic stress in yeast, mechanical stretch activates SAPKs in cardiac myocytes without the participation of angiotensin II. These results suggest that the activation of SAPKs may regulate gene expression during mechanical stress-induced cardiac hypertrophy.
Komuro
I
I
Department of Medicine III, University of Tokyo School of Medicine, Japan.
Kudo
S
S
Yamazaki
T
T
Zou
Y
Y
Shiojima
I
I
Yazaki
Y
Y
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008465:Mechanoreceptors / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases; D009206:Myocardium / Q000201:enzymology*; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013314:Stress, Mechanical; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection
D018808:Transcription Factor AP-1; D000804:Angiotensin II; D011494:Protein Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium