title: Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells.
abstract: Angiotensin II (Ang II) is now believed to play a critical role in the pathogenesis of hypertrophy and/or hyperplasia of vascular smooth muscle cells (VSMCs). Several G(i)- and G(q)-coupled receptors, including the Ang II type 1 (AT(1)) receptor, activate Rho and Rho-associated kinase in Swiss 3T3 cells and cardiac myocytes. However, little is known about the role of Rho-kinase in Ang II-induced vascular hypertrophy in VSMCs. In the present study, we explored the role of Rho and Rho-kinase in Ang II-induced protein synthesis in VSMCs. In unstimulated cells, RhoA was observed predominantly in the cytosolic fraction, but it was translocated in part to the particulate fraction in response to Ang II (100 nmol/L). This effect was completely blocked by the AT(1) receptor blocker candesartan but not by the Ang II type 2 (AT(2)) receptor antagonist PD123319. Botulinum C(3) exoenzyme, which inactivated RhoA, attenuated Ang II-induced [(3)H]leucine incorporation. The specific Rho-kinase inhibitor, Y-27632, dose-dependently abolished Ang II-induced protein synthesis and also suppressed Ang II-induced c-fos mRNA expression. On the other hand, Y-27632 had no effect on Ang II-stimulated phosphorylation of p70 S6 kinase and extracellular signal-regulated kinase 1/2, which are reported to be involved in Ang II-induced protein synthesis, nor had it any effect on the Ang II-induced phosphorylation of PHAS-I, a heat- and acid-stable eIF-4E-binding protein. The phosphorylation of PHAS-I is regulating for translation initiation. These observations suggest that the Rho, Rho-kinase, and c-fos pathways may play a role in Ang II-induced hypertrophic changes of VSMCs through a novel pathway.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA. Yamakat@med.yokohama-cu.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Yamakawa
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Numaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Yamakawa
authors.forename: E D
authors.initials: ED
authors.lastname: Motley
authors.forename: S
authors.initials: S
authors.lastname: Ichihara
authors.forename: T
authors.initials: T
authors.lastname: Inagami
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001692:Biological Transport / Q000187:drug effects; D001905:Botulinum Toxins; D002352:Carrier Proteins; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006984:Hypertrophy; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000493:pharmacokinetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D012333:RNA, Messenger; D000804:Angiotensin II; C108830:Y 27632; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D054460:rho-Associated Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D001905:Botulinum Toxins; D020741:rho GTP-Binding Proteins; D007930:Leucine