doi: 10.1161/hy0202.102699
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(Hypertension. 2002;39:233.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Integrins Play a Critical Role in Mechanical Stress–Induced p38 MAPK Activation
From the Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine (R.A., M.T., R.N.), Tokyo, Japan; Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine (T.N., Y.Z., H.A., H.T., I.K.), Chiba; Japan; Department of Cardiovascular Medicine, Kanazawa Medical University (S.K.), Ishikawa, Japan; and Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine (M.T.), Fukuoka, Japan.
Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail komuro-tky{at}umin.ac.jp
Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal–regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH2-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch–induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.
Key Words: hypertrophy, cardiac • myocytes • stress, mechanical • integrins • protein kinases
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