(Hypertension. 2000;35:313.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Involvement of Rho-Kinase in Angiotensin II–Induced Hypertrophy of Rat Vascular Smooth Muscle Cells
From the Department of Biochemistry (T.Y., K.N., Y.Y., S.I., T.I.), Vanderbilt University School of Medicine, Nashville, Tenn; the 3rd Department of Internal Medicine (T.Y., H.S.) and Department of Dermatology (Y.Y.), Yokohama City University School of Medicine, Yokohama, Japan; Neurobiology of Aging Laboratories (S.T.), Mt. Sinai School of Medicine, New York, NY; and the Department of Anatomy and Physiology (E.D.M.), Meharry Medical College, Nashville, Tenn.
Correspondence to Dr Tadashi Yamakawa, 3rd Department of Internal Medicine, Yokohama City University School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, 236-0004, Japan. E-mail Yamakat{at}med.yokohama-cu.ac.jp
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 Gi- and Gq-coupled receptors, including the Ang II type 1 (AT1) 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 AT1 receptor blocker candesartan but not by the Ang II type 2 (AT2) receptor antagonist PD123319. Botulinum C3 exoenzyme, which inactivated RhoA, attenuated Ang II–induced [3H]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.
Key Words: angiotensin II • hypertrophy • G proteins
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