© 1999 American Heart Association, Inc.
Original Contribution |
Rho and Rho Kinase Mediate Thrombin-Stimulated Vascular Smooth Muscle Cell DNA Synthesis and Migration
From the University of California, San Diego, Department of Pharmacology, La Jolla.
Correspondence to Joan Heller Brown, University of California, San Diego, Department of Pharmacology, 9500 Gilman Dr, La Jolla, CA 92093-0636. E-mail jhbrown{at}ucsd.edu
Abstract—Aberrant
regulation of smooth muscle cell proliferation and migration is
associated with the pathophysiology of vascular disorders such as
hypertension, atherosclerosis, restenosis, and
graft rejection. To elucidate molecular mechanisms that regulate
proliferation and migration of vascular smooth muscle cells, we
determined whether signaling through the small G protein Rho is
involved in thrombin- and phenylephrine-stimulated
proliferation and migration of rat aortic smooth muscle cells (RASMCs).
Thrombin and the thrombin peptide SFLLRNP stimulated DNA synthesis of
RASMCs as measured by [3H]thymidine incorporation. Both
ligands also increased cell migration as measured by the Boyden chamber
method. L-Phenylephrine failed to induce either
of these responses but increased inositol phosphate accumulation and
mitogen-activated protein kinase activation in these cells,
which indicated that the cells were responsive to
1-adrenergic stimulation. The C3 exoenzyme, which
ADP-ribosylates and inactivates Rho, fully inhibited both
thrombin-stimulated proliferation and migration but had no effect on
inositol phosphate accumulation. In addition, Y-27632, an
inhibitor of the Rho effector p160ROCK/Rho kinase,
decreased thrombin-stimulated DNA synthesis and migration. To directly
examine Rho activation, Rho-[35S]GTP
S binding was
measured. The addition of the thrombin peptide SFLLRNP, but not
phenylephrine, to RASMC lysates resulted in a significant
increase in Rho-[35S]GTPS binding. Thrombin and
SFLLRNP, but not phenylephrine, also increased
membrane-associated Rho in intact RASMCs, consistent with
selective activation of Rho by thrombin. These results indicate that
thrombin activates Rho in RASMCs and establish Rho as a
critical mediator of thrombin receptor effects on DNA synthesis and
cell migration in these cells.
Key Words: Rho • thrombin • vascular smooth muscle • DNA synthesis • cell migration
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U. Laufs, M. Endres, F. Custodis, K. Gertz, G. Nickenig, J. K. Liao, and M. Bohm Suppression of Endothelial Nitric Oxide Production After Withdrawal of Statin Treatment Is Mediated by Negative Feedback Regulation of Rho GTPase Gene Transcription Circulation, December 19, 2000; 102(25): 3104 - 3110. [Abstract] [Full Text] [PDF]
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H. Chen, U. Ikeda, M. Shimpo, M. Ikeda, S. Minota, and K. Shimada Fluvastatin Upregulates Inducible Nitric Oxide Synthase Expression in Cytokine-Stimulated Vascular Smooth Muscle Cells Hypertension, December 1, 2000; 36(6): 923 - 928. [Abstract] [Full Text] [PDF]
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D. E. Vatner and D. L. Kunze Prologue: low-molecular-weight GTPases in the heart and circulation Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1733 - H1735. [Full Text] [PDF]
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Y. Eto, H. Shimokawa, J. Hiroki, K. Morishige, T. Kandabashi, Y. Matsumoto, M. Amano, M. Hoshijima, K. Kaibuchi, and A. Takeshita Gene transfer of dominant negative Rho kinase suppresses neointimal formation after balloon injury in pigs Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1744 - H1750. [Abstract] [Full Text] [PDF]
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V. Sauzeau, H. le Jeune, C. Cario-Toumaniantz, N. Vaillant, A.-P. Gadeau, C. Desgranges, E. Scalbert, P. Chardin, P. Pacaud, and G. Loirand P2Y1, P2Y2, P2Y4, and P2Y6 receptors are coupled to Rho and Rho kinase activation in vascular myocytes Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1751 - H1761. [Abstract] [Full Text] [PDF]
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M. R. Morissette, V. P. Sah, C. C. Glembotski, and J. H. Brown The Rho effector, PKN, regulates ANF gene transcription in cardiomyocytes through a serum response element Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1769 - H1774. [Abstract] [Full Text] [PDF]
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N. Sawada, H. Itoh, K. Ueyama, J. Yamashita, K. Doi, T.-H. Chun, M. Inoue, K. Masatsugu, T. Saito, Y. Fukunaga, et al. Inhibition of Rho-Associated Kinase Results in Suppression of Neointimal Formation of Balloon-Injured Arteries Circulation, May 2, 2000; 101(17): 2030 - 2033. [Abstract] [Full Text] [PDF]
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T. Ishizaki, M. Uehata, I. Tamechika, J. Keel, K. Nonomura, M. Maekawa, and S. Narumiya Pharmacological Properties of Y-27632, a Specific Inhibitor of Rho-Associated Kinases Mol. Pharmacol., May 1, 2000; 57(5): 976 - 983. [Abstract] [Full Text]
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 A. P Somlyo and A. V Somlyo Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II J. Physiol., January 15, 2000; 522(2): 177 - 185. [Abstract] [Full Text] [PDF]
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 D Nath, P. Slocombe, A Webster, P. Stephens, A. Docherty, and G Murphy Meltrin gamma(ADAM-9) mediates cellular adhesion through alpha(6)beta(1 )integrin, leading to a marked induction of fibroblast cell motility J. Cell Sci., January 6, 2000; 113(12): 2319 - 2328. [Abstract] [PDF]
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T. Yamakawa, S.-i. Tanaka, K. Numaguchi, Y. Yamakawa, E. D. Motley, S. Ichihara, and T. Inagami Involvement of Rho-Kinase in Angiotensin II-Induced Hypertrophy of Rat Vascular Smooth Muscle Cells Hypertension, January 1, 2000; 35(1): 313 - 318. [Abstract] [Full Text] [PDF]
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V. Sauzeau, H. Le Jeune, C. Cario-Toumaniantz, A. Smolenski, S. M. Lohmann, J. Bertoglio, P. Chardin, P. Pacaud, and G. Loirand Cyclic GMP-dependent Protein Kinase Signaling Pathway Inhibits RhoA-induced Ca2+ Sensitization of Contraction in Vascular Smooth Muscle J. Biol. Chem., July 7, 2000; 275(28): 21722 - 21729. [Abstract] [Full Text] [PDF]
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C. P. Mack, A. V. Somlyo, M. Hautmann, A. P. Somlyo, and G. K. Owens Smooth Muscle Differentiation Marker Gene Expression Is Regulated by RhoA-mediated Actin Polymerization J. Biol. Chem., January 5, 2001; 276(1): 341 - 347. [Abstract] [Full Text] [PDF]
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S. A. Sagi, T. M. Seasholtz, M. Kobiashvili, B. A. Wilson, D. Toksoz, and J. H. Brown Physical and Functional Interactions of Galpha q with Rho and Its Exchange Factors J. Biol. Chem., April 27, 2001; 276(18): 15445 - 15452. [Abstract] [Full Text] [PDF]
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T. M. Seasholtz, T. Zhang, M. R. Morissette, A. L. Howes, A. H. Yang, and J. H. Brown Increased Expression and Activity of RhoA Are Associated With Increased DNA Synthesis and Reduced p27Kip1 Expression in the Vasculature of Hypertensive Rats Circ. Res., September 14, 2001; 89(6): 488 - 495. [Abstract] [Full Text] [PDF]
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M. Eto, C. Barandier, L. Rathgeb, T. Kozai, H. Joch, Z. Yang, and T. F. Luscher Thrombin Suppresses Endothelial Nitric Oxide Synthase and Upregulates Endothelin-Converting Enzyme-1 Expression by Distinct Pathways: Role of Rho/ROCK and Mitogen-Activated Protein Kinase Circ. Res., September 28, 2001; 89(7): 583 - 590. [Abstract] [Full Text] [PDF]
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H. Chaulet, C. Desgranges, M.-A. Renault, F. Dupuch, G. Ezan, F. Peiretti, G. Loirand, P. Pacaud, and A.-P. Gadeau Extracellular Nucleotides Induce Arterial Smooth Muscle Cell Migration Via Osteopontin Circ. Res., October 26, 2001; 89(9): 772 - 778. [Abstract] [Full Text] [PDF]
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