Contribution of Rho A and Rho kinase to platelet-derived growth factor-BB-induced proliferation of vascular smooth muscle cells.
In order to identify small G protein (s) which contributes to the proliferation of vascular smooth muscle cells (VSMCs), we examined the effect of an HMG-CoA reductase inhibitor (cerivastatin), a farnesyltransferase inhibitor (FTI-277), a geranyl geranyl transferase inhibitor (GGTI-286) and a Rho kinase inhibitor (Y-27632) on the proliferation of cultured rat VSMCs stimulated with 20ng/ml platelet-derived growth factor (PDGF)-BB. Cerivastatin and GGTI-286, but not FTI-277, suppressed the PDGF-BB-induced activation of extracellular signal related kinase (ERK1/2). The inhibitory effect of cerivastatin on the PDGF-BB-induced activation of ERK1/2 was fully recovered by the addition of geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP). Cerivastatin and GGTI-286, but not FTI-277, suppressed the PDGF-BB-induced [3H] thymidine incorporation and activation of ornitine decarboxylase (ODC), both of which were fully recovered by the addition of GGPP, but not FPP. These data indicate that the PDGF-BB-induced activation of ERK1/2 and proliferation of VSMCs depend upon geranylgeranylated small G protein. Immunoblotting analysis revealed the upregulation of Rho A protein in the membrane fractions of VSMCs stimulated by PDGF-BB. Furthermore, Y-27632 suppressed the PDGF-BB-induced activation of ERK1/2 and proliferation of VSMCs. On the basis of these data, we conclude that PDGF-BB stimulates the proliferation of VSMCs via the activation of Rho A. Rho kinase plays an important role in this process as an effector of Rho A.
Kamiyama
Masumi
M
Division of Diabetes and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan.
Utsunomiya
Kazunori
K
Taniguchi
Kanta
K
Yokota
Tamotsu
T
Kurata
Hideaki
H
Tajima
Naoko
N
Kondo
Kazuo
K
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000577:Amides; D004791:Enzyme Inhibitors; C096856:FTI 277; C437105:GGTI 286; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; C108830:Y 27632; D008715:Methionine; C086276:cerivastatin; 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; D020742:rhoA GTP-Binding Protein; D007930:Leucine