Atorvastatin induces thrombomodulin expression in the aorta of cholesterol-fed rabbits and in TNFα-treated human aortic endothelial cells

Shing Jong Lin, Fang Yu Hsieh, Yung Hsiang Chen, Chia Chi Lin, I. I. Kuan, Shu Huei Wang, Chau Chung Wu, Hsiung-Fei Chien, Fen Yen Lin, Yuh Lien Chen

Research output: Contribution to journalArticle

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Abstract

Expression of functionally active thrombomodulin (TM) on endothelial cells is critical for vascular thromboresistance. 3-Hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can protect the vasculature from inflammation and atherosclerosis caused by cholesterol-dependent and cholesterolindependent mechanisms. In the present study, the effects of atorvastatin on TM expression in the aorta of cholesterol-fed rabbits and in TNFα-treated human aortic endothelial cells (HAECs) were investigated. When rabbits were fed a 0.5% cholesterol diet with and without supplementation with atorvastatin for 9 weeks, the neointimal area in the thoracic aorta of the atorvastatin-treated group was significantly reduced and there was significant induction of TM protein expression. In HAECs, TNFα treatment decreased the expression of TM in a time- and dose-dependent manner and atorvastatin pretreatment upregulated the expression of TM mRNA and protein in HAECs with or without TNFα treatment. Atorvastatin also inhibited monocyte adhesion to control and TNFα-treated HAECs via TM expression. ERK1/2 phosphorylation was significantly reduced by 24 h pretreatment with atorvastatin, whereas TNFα increased the phosphorylation of the MAPKs, p38, JNK, and ERK1/2. Blocking the transcriptional activation of NF-kB and nuclear translocation of NF-kB p65 prevented the TNFα-induced downregulation of TM. Atorvastatin regulated TM expression in control and TNFα-treated HAECs by inhibiting the activation of ERK and NF-kB. The increase in endothelial TM activity in response to atorvastatin constitutes an important pleiotropic effect of this commonly used compound and may be of clinical significance in cardiovascular disorders in which deficient endothelial TM plays a pathophysiTological role.

Original languageEnglish
Pages (from-to)1147-1159
Number of pages13
JournalHistology and Histopathology
Volume24
Issue number9
Publication statusPublished - Sep 2009

Fingerprint

Thrombomodulin
Aorta
Endothelial Cells
Cholesterol
Rabbits
NF-kappa B
Phosphorylation
Atorvastatin Calcium
Hydroxymethylglutaryl-CoA Reductase Inhibitors
p38 Mitogen-Activated Protein Kinases
Coenzyme A
Thoracic Aorta
Hydroxyl Radical
Transcriptional Activation
Blood Vessels
Monocytes
Atherosclerosis
Oxidoreductases
Proteins
Down-Regulation

Keywords

  • Atorvastatin
  • Cholesterol-fed rabbit
  • Endothelial cells
  • MAPKs
  • Thrombomodulin

ASJC Scopus subject areas

  • Histology
  • Pathology and Forensic Medicine

Cite this

Lin, S. J., Hsieh, F. Y., Chen, Y. H., Lin, C. C., Kuan, I. I., Wang, S. H., ... Chen, Y. L. (2009). Atorvastatin induces thrombomodulin expression in the aorta of cholesterol-fed rabbits and in TNFα-treated human aortic endothelial cells. Histology and Histopathology, 24(9), 1147-1159.

Atorvastatin induces thrombomodulin expression in the aorta of cholesterol-fed rabbits and in TNFα-treated human aortic endothelial cells. / Lin, Shing Jong; Hsieh, Fang Yu; Chen, Yung Hsiang; Lin, Chia Chi; Kuan, I. I.; Wang, Shu Huei; Wu, Chau Chung; Chien, Hsiung-Fei; Lin, Fen Yen; Chen, Yuh Lien.

In: Histology and Histopathology, Vol. 24, No. 9, 09.2009, p. 1147-1159.

Research output: Contribution to journalArticle

Lin, Shing Jong ; Hsieh, Fang Yu ; Chen, Yung Hsiang ; Lin, Chia Chi ; Kuan, I. I. ; Wang, Shu Huei ; Wu, Chau Chung ; Chien, Hsiung-Fei ; Lin, Fen Yen ; Chen, Yuh Lien. / Atorvastatin induces thrombomodulin expression in the aorta of cholesterol-fed rabbits and in TNFα-treated human aortic endothelial cells. In: Histology and Histopathology. 2009 ; Vol. 24, No. 9. pp. 1147-1159.
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AU - Lin, Chia Chi

AU - Kuan, I. I.

AU - Wang, Shu Huei

AU - Wu, Chau Chung

AU - Chien, Hsiung-Fei

AU - Lin, Fen Yen

AU - Chen, Yuh Lien

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N2 - Expression of functionally active thrombomodulin (TM) on endothelial cells is critical for vascular thromboresistance. 3-Hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can protect the vasculature from inflammation and atherosclerosis caused by cholesterol-dependent and cholesterolindependent mechanisms. In the present study, the effects of atorvastatin on TM expression in the aorta of cholesterol-fed rabbits and in TNFα-treated human aortic endothelial cells (HAECs) were investigated. When rabbits were fed a 0.5% cholesterol diet with and without supplementation with atorvastatin for 9 weeks, the neointimal area in the thoracic aorta of the atorvastatin-treated group was significantly reduced and there was significant induction of TM protein expression. In HAECs, TNFα treatment decreased the expression of TM in a time- and dose-dependent manner and atorvastatin pretreatment upregulated the expression of TM mRNA and protein in HAECs with or without TNFα treatment. Atorvastatin also inhibited monocyte adhesion to control and TNFα-treated HAECs via TM expression. ERK1/2 phosphorylation was significantly reduced by 24 h pretreatment with atorvastatin, whereas TNFα increased the phosphorylation of the MAPKs, p38, JNK, and ERK1/2. Blocking the transcriptional activation of NF-kB and nuclear translocation of NF-kB p65 prevented the TNFα-induced downregulation of TM. Atorvastatin regulated TM expression in control and TNFα-treated HAECs by inhibiting the activation of ERK and NF-kB. The increase in endothelial TM activity in response to atorvastatin constitutes an important pleiotropic effect of this commonly used compound and may be of clinical significance in cardiovascular disorders in which deficient endothelial TM plays a pathophysiTological role.

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