© 1999 American Heart Association, Inc.
Original Contribution |
Rho Family Small G Proteins Play Critical Roles in Mechanical Stress–Induced Hypertrophic Responses in Cardiac Myocytes
From the Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine (R.A., I.K., T.Y., Y.Z., S.K., W.Z., T.K., Y.Y.), and the Health Service Center (T.Y.), University of Tokyo, Tokyo, Japan.
Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky{at}umin.u-tokyo.ac.jp
Abstract—Mechanical stress
induces a variety of hypertrophic responses, such as activation of
protein kinases, reprogramming of gene expression, and an increase in
protein synthesis. In the present study, to elucidate how
mechanical stress induces such events, we examined the role of Rho
family small GTP-binding proteins (G proteins) in mechanical
stress–induced cardiac hypertrophy. Treatment of neonatal
rat cardiomyocytes with the C3 exoenzyme, which abrogates
Rho functions, suppressed stretch-induced activation of extracellular
signal–regulated protein kinases (ERKs). Overexpression of the Rho GDP
dissociation inhibitor (Rho-GDI), dominant-negative mutants
of RhoA (DNRhoA), or DNRac1 significantly inhibited stretch-induced
activation of transfected ERK2. Overexpression of constitutively active
mutants of RhoA slightly activated ERK2 in cardiac myocytes.
Overexpression of C-terminal Src kinase, which inhibits
functions of the Src family of tyrosine kinases, or overexpression of
DNRas had no effect on stretch-induced activation of transfected ERK2.
The promoter activity of skeletal 
-actin and c-fos
genes was increased by stretch, and these increases were completely
inhibited by either cotransfection of Rho-GDI or pretreatment with C3
exoenzyme. Mechanical stretch increased phenylalanine incorporation
into cardiac myocytes by 
1.5-fold compared with control, and this
increase was also significantly suppressed by pretreatment with C3
exoenzyme. Overexpression of Rho-GDI or DNRhoA did not affect
angiotensin II–induced activation of ERK. ERKs were
activated by culture media conditioned by stretch of
cardiomyocytes without any treatment, but not of
cardiomyocytes with pretreatment by C3 exoenzyme. These
results suggest that the Rho family of small G proteins plays critical
roles in mechanical stress–induced hypertrophic responses.
Key Words: Rho • mechanical stress • cardiac hypertrophy
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