Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin

Naoya Takeda, Masashi Kondo, Satoru Ito, Yasushi Ito, Kaoru Shimokata, Hiroaki Kume

研究成果: Article

108 引用 (Scopus)

抄録

Enhanced proliferation of smooth muscle cells contributes to airway remodeling of bronchial asthma. Recently, statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have been shown to inhibit proliferation of both vascular and airway smooth muscle cells independently of lowering cholesterol. However, the mechanisms remain to be elucidated. The purpose of this study was to determine molecular processes by which statins inhibit proliferation of human bronchial smooth muscle cells. Simvastatin (0.1-1.0 μM) significantly inhibited cell proliferation and DNA synthesis induced by FBS in a concentration-dependent manner. The inhibitory effects of simvastatin were antagonized by mevalonate and geranylgeranylpyrophosphate, whereas the effects were not affected by squalene and farnesylpyrophosphate. The antiproliferative effects of simvastatin were mimicked by GGTI-286, a geranylgeranyltransferase-I inhibitor, C3 exoenzyme, an inhibitor of Rho, and Y-27632, an inhibitor of Rho-kinase, a target protein of RhoA. Western blot analysis showed that the level of membrane localization of RhoA (active Rho) was markedly increased by FBS, and that the level of active RhoA increased by FBS was reduced by simvastatin. Moreover, the inhibitory effect of simvastatin on FBS-induced RhoA activation was also antagonized by geranylgeranylpyrophosphate, but not by farnesylpyrophosphate. Because these isoprenoids are required for prenylation of small G proteins RhoA and Ras, respectively, the present results demonstrate that an inhibition in airway smooth muscle cell proliferation by simvastatin is due to prevention of geranylgeranylation of RhoA, not farnesylation of Ras. Therefore, statins may have therapeutic potential for prohibiting airway remodeling in bronchial asthma.

元の言語English
ページ(範囲)722-729
ページ数8
ジャーナルAmerican Journal of Respiratory Cell and Molecular Biology
35
発行部数6
DOI
出版物ステータスPublished - 01-12-2006

Fingerprint

Simvastatin
Cell proliferation
Smooth Muscle
Muscle
Cell Proliferation
Prenylation
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Smooth Muscle Myocytes
Airway Remodeling
Cells
Asthma
rhoA GTP-Binding Protein
Squalene
rho-Associated Kinases
Mevalonic Acid
Monomeric GTP-Binding Proteins
Terpenes
Vascular Smooth Muscle
Oxidoreductases
Western Blotting

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

これを引用

Takeda, Naoya ; Kondo, Masashi ; Ito, Satoru ; Ito, Yasushi ; Shimokata, Kaoru ; Kume, Hiroaki. / Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin. :: American Journal of Respiratory Cell and Molecular Biology. 2006 ; 巻 35, 番号 6. pp. 722-729.
@article{f1da9ad1153b40ceb2fa00452beeafee,
title = "Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin",
abstract = "Enhanced proliferation of smooth muscle cells contributes to airway remodeling of bronchial asthma. Recently, statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have been shown to inhibit proliferation of both vascular and airway smooth muscle cells independently of lowering cholesterol. However, the mechanisms remain to be elucidated. The purpose of this study was to determine molecular processes by which statins inhibit proliferation of human bronchial smooth muscle cells. Simvastatin (0.1-1.0 μM) significantly inhibited cell proliferation and DNA synthesis induced by FBS in a concentration-dependent manner. The inhibitory effects of simvastatin were antagonized by mevalonate and geranylgeranylpyrophosphate, whereas the effects were not affected by squalene and farnesylpyrophosphate. The antiproliferative effects of simvastatin were mimicked by GGTI-286, a geranylgeranyltransferase-I inhibitor, C3 exoenzyme, an inhibitor of Rho, and Y-27632, an inhibitor of Rho-kinase, a target protein of RhoA. Western blot analysis showed that the level of membrane localization of RhoA (active Rho) was markedly increased by FBS, and that the level of active RhoA increased by FBS was reduced by simvastatin. Moreover, the inhibitory effect of simvastatin on FBS-induced RhoA activation was also antagonized by geranylgeranylpyrophosphate, but not by farnesylpyrophosphate. Because these isoprenoids are required for prenylation of small G proteins RhoA and Ras, respectively, the present results demonstrate that an inhibition in airway smooth muscle cell proliferation by simvastatin is due to prevention of geranylgeranylation of RhoA, not farnesylation of Ras. Therefore, statins may have therapeutic potential for prohibiting airway remodeling in bronchial asthma.",
author = "Naoya Takeda and Masashi Kondo and Satoru Ito and Yasushi Ito and Kaoru Shimokata and Hiroaki Kume",
year = "2006",
month = "12",
day = "1",
doi = "10.1165/rcmb.2006-0034OC",
language = "English",
volume = "35",
pages = "722--729",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "6",

}

Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin. / Takeda, Naoya; Kondo, Masashi; Ito, Satoru; Ito, Yasushi; Shimokata, Kaoru; Kume, Hiroaki.

:: American Journal of Respiratory Cell and Molecular Biology, 巻 35, 番号 6, 01.12.2006, p. 722-729.

研究成果: Article

TY - JOUR

T1 - Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin

AU - Takeda, Naoya

AU - Kondo, Masashi

AU - Ito, Satoru

AU - Ito, Yasushi

AU - Shimokata, Kaoru

AU - Kume, Hiroaki

PY - 2006/12/1

Y1 - 2006/12/1

N2 - Enhanced proliferation of smooth muscle cells contributes to airway remodeling of bronchial asthma. Recently, statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have been shown to inhibit proliferation of both vascular and airway smooth muscle cells independently of lowering cholesterol. However, the mechanisms remain to be elucidated. The purpose of this study was to determine molecular processes by which statins inhibit proliferation of human bronchial smooth muscle cells. Simvastatin (0.1-1.0 μM) significantly inhibited cell proliferation and DNA synthesis induced by FBS in a concentration-dependent manner. The inhibitory effects of simvastatin were antagonized by mevalonate and geranylgeranylpyrophosphate, whereas the effects were not affected by squalene and farnesylpyrophosphate. The antiproliferative effects of simvastatin were mimicked by GGTI-286, a geranylgeranyltransferase-I inhibitor, C3 exoenzyme, an inhibitor of Rho, and Y-27632, an inhibitor of Rho-kinase, a target protein of RhoA. Western blot analysis showed that the level of membrane localization of RhoA (active Rho) was markedly increased by FBS, and that the level of active RhoA increased by FBS was reduced by simvastatin. Moreover, the inhibitory effect of simvastatin on FBS-induced RhoA activation was also antagonized by geranylgeranylpyrophosphate, but not by farnesylpyrophosphate. Because these isoprenoids are required for prenylation of small G proteins RhoA and Ras, respectively, the present results demonstrate that an inhibition in airway smooth muscle cell proliferation by simvastatin is due to prevention of geranylgeranylation of RhoA, not farnesylation of Ras. Therefore, statins may have therapeutic potential for prohibiting airway remodeling in bronchial asthma.

AB - Enhanced proliferation of smooth muscle cells contributes to airway remodeling of bronchial asthma. Recently, statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have been shown to inhibit proliferation of both vascular and airway smooth muscle cells independently of lowering cholesterol. However, the mechanisms remain to be elucidated. The purpose of this study was to determine molecular processes by which statins inhibit proliferation of human bronchial smooth muscle cells. Simvastatin (0.1-1.0 μM) significantly inhibited cell proliferation and DNA synthesis induced by FBS in a concentration-dependent manner. The inhibitory effects of simvastatin were antagonized by mevalonate and geranylgeranylpyrophosphate, whereas the effects were not affected by squalene and farnesylpyrophosphate. The antiproliferative effects of simvastatin were mimicked by GGTI-286, a geranylgeranyltransferase-I inhibitor, C3 exoenzyme, an inhibitor of Rho, and Y-27632, an inhibitor of Rho-kinase, a target protein of RhoA. Western blot analysis showed that the level of membrane localization of RhoA (active Rho) was markedly increased by FBS, and that the level of active RhoA increased by FBS was reduced by simvastatin. Moreover, the inhibitory effect of simvastatin on FBS-induced RhoA activation was also antagonized by geranylgeranylpyrophosphate, but not by farnesylpyrophosphate. Because these isoprenoids are required for prenylation of small G proteins RhoA and Ras, respectively, the present results demonstrate that an inhibition in airway smooth muscle cell proliferation by simvastatin is due to prevention of geranylgeranylation of RhoA, not farnesylation of Ras. Therefore, statins may have therapeutic potential for prohibiting airway remodeling in bronchial asthma.

UR - http://www.scopus.com/inward/record.url?scp=33750468907&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750468907&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2006-0034OC

DO - 10.1165/rcmb.2006-0034OC

M3 - Article

VL - 35

SP - 722

EP - 729

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 6

ER -