Rho/ROCK pathway contributes to the activation of extracellular signal-regulated kinase/GATA-4 during myocardial cell hypertrophy.
The low molecular weight GTPase Rho mediates a variety of cytoskeleton-dependent cell functions and stretch- and G(q) protein-induced hypertrophic responses in cardiac myocytes. Although ROCK, one of Rho's effectors, has been suggested to mediate hypertrophic signals, the relationship of Rho/ROCK with downstream signals is unknown. A zinc finger transcription factor, GATA-4, is activated by extracellular signal-regulated kinase 1/2 and is required for the up-regulation of the endothelin-1 gene during myocardial cell hypertrophy. However, it is unknown whether Rho/ROCK signals are linked to downstream GATA-4. By transient transfection assays using a dominant-negative mutant and an activated derivative of ROCK-I, we showed that ROCK-I participates in GATA-4-dependent endothelin-1 transcription. Inhibition of the Rho/ROCK pathway by Y-27632, a selective inhibitor of ROCK, suppressed phenylephrine-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 and increased the DNA binding activity of cardiac GATA-4. Interestingly, latrunculin B, which inhibits actin polymerization, also prevents phenylephrine-induced responses. These findings demonstrate that the Rho/ROCK pathway is linked to downstream GATA-4 via the activation of extracellular signal-regulated kinases during myocardial cell hypertrophy. The results also suggest that changes in actin dynamics provide a convergence point for Rho/ROCK to the downstream signals during this process.
Yanazume
Tetsuhiko
T
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Hasegawa
Koji
K
Wada
Hiromichi
H
Morimoto
Tatsuya
T
Abe
Mitsuru
M
Kawamura
Teruhisa
T
Sasayama
Shigetake
S
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D019556:COS Cells; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D050991:GATA4 Transcription Factor; D006984:Hypertrophy; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000166:cytology*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016335:Zinc Fingers; D054460:rho-Associated Kinases
D000199:Actins; D000577:Amides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D013844:Thiazoles; D053778:Thiazolidines; D014157:Transcription Factors; C108830:Y 27632; D010656:Phenylephrine; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C037068:latrunculin B