HMG CoA reductase inhibitor suppresses the expression of tissue factor and plasminogen activator inhibitor-1 induced by angiotensin II in cultured rat aortic endothelial cells

被引：56

作者：

Kunieda, Y ^{[1
]}

Nakagawa, K ^{[1
]}

Nishimura, H ^{[1
]}

Kato, H ^{[1
]}

Ukimura, N ^{[1
]}

Yano, S ^{[1
]}

Kawano, H ^{[1
]}

Kimura, S ^{[1
]}

Nakagawa, M ^{[1
]}

Tsuji, H ^{[1
]}

机构：

[1] Kyoto Prefectural Univ Med, Dept Med 2, Kamigyo Ku, Kyoto 6028566, Japan

来源：

THROMBOSIS RESEARCH | 2003年 / 110卷 / 04期

关键词：

HMG CoA reductase inhibitor (HRI); tissue factor (TF); plasminogen activator inhibitor-1 (PAI-1); endothelial cells; Rho/Rho kinase;

D O I：

10.1016/S0049-3848(03)00346-3

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: It has been demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) reduce the incidence of acute cardiovascular events in patients with hyperlipidemia. Recent reports have shown that the protective effects of these drugs against cardiovascular events are also observed in patients without hyperlipidemia, but the mechanism of this favorable effect still remains unclear. In this study, the effects of HRIs on the endothelial regulation of thrombus formation were elucidated. Methods and results: The mRNA and protein expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) induced by angiotensin II (Ang II) were evaluated in cultured rat aortic endothelial cells. Pretreatment with simvastatin (0.03 - 3 mug/ml) significantly inhibited TF and PAI-1 induction by Ang II in a dose- and time-dependent manner. These inhibitions were significantly attenuated by mevalonic acid or geranylgeranyl pyrophosphate. Both Rho inhibitor, C3 exoenzyme, and Rho kinase inhibitor, Y-27632, mimicked the inhibitory effects of simvastatin against TF and PAI-1 induced by Ang II. This result suggested that the Rho/Rho kinase pathway is related to the TF and PAI-1 induction by Ang II. Conclusion: It was indicated that simvastatin maintains endothelial cells to be antithrombotic by inhibiting TF and PAI-1 expression via the Rho/Rho kinase pathways in which Ang II induces TF and PAI-1 expression. These observations explain, at least partly, the mechanism of the favorable effects of simvastatin in reducing the thrombotic events. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：227 / 234

页数：8

共 32 条

[21] Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats [J].

Pruefer, D ;

Scalia, R ;

Lefer, AM .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1999, 19 (12) :2894-2900

[22]

SCARPATI EM, 1989, J BIOL CHEM, V264, P20705

[23] INCREASED TYPE-1 PLASMINOGEN-ACTIVATOR INHIBITOR GENE-EXPRESSION IN ATHEROSCLEROTIC HUMAN ARTERIES [J].

SCHNEIDERMAN, J ;

SAWDEY, MS ;

KEETON, MR ;

BORDIN, GM ;

BERNSTEIN, EF ;

DILLEY, RB ;

LOSKUTOFF, DJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (15) :6998-7002

[24]

Shibata R, 2001, CIRCULATION, V103, P284

[25] Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial infarction [J].

Soejima, H ;

Ogawa, H ;

Yasue, H ;

Kaikita, K ;

Takazoe, K ;

Nishiyama, K ;

Misumi, K ;

Miyamoto, S ;

Yoshimura, M ;

Kugiyama, K ;

Nakamura, S ;

Tsuji, I .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1999, 34 (04) :983-988

[26]

SPRENGERS ED, 1987, BLOOD, V69, P381

[27]

Terano T, 1998, J Atheroscler Thromb, V5, P1

[28]

Tonkin A, 1998, NEW ENGL J MED, V339, P1349

[29] Tissue factor in atherosclerosis [J].

Tremoli, E ;

Camera, M ;

Toschi, V ;

Colli, S .

ATHEROSCLEROSIS, 1999, 144 (02) :273-283

[30] Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension [J].

Uehata, M ;

Ishizaki, T ;

Satoh, H ;

Ono, T ;

Kawahara, T ;

Morishita, T ;

Tamakawa, H ;

Yamagami, K ;

Inui, J ;

Maekawa, M ;

Narumiya, S .

NATURE, 1997, 389 (6654) :990-994

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