Abstract
Expression of functionally active thrombomodulin (TM) on the luminal surface of endothelial cells is critical for vascular thromboresistance. The 3-hydroxyl-3-methyl coenzyme A reductase inhibitor, pravastatin, can protect the vasculature in a manner that is independent of its lipid-lowering activity. We examined the effect of pravastatin on TM expression by human aortic endothelial cells (HAECs) with subsequent tumor necrosis factor α (TNFα) stimulation and investigated the signaling pathways involved. TNFα treatment attenuated TM expression in HAECs in a time-dependent manner. Pravastatin upregulated TM levels in TNFα-treated HAECs. Specific inhibition of geranylgeranyl-transferase-I or the Rho family by GGTI-286 or TcdB, respectively, enhanced TM expression in TNFα-treated HAECs, whereas MAP kinase inhibitors, inactivation of Rho by Clostridium botulinum C3 exoenzyme, or the Rho kinase inhibitor, Y-27632, had no effect. In TNFα-treated HAECs, pravastatin inhibited Rac1 and Cdc42 activation and their translocation to the cell membrane. Blocking the transcriptional activation of NF-κB prevented the TNFα-induced downregulation of TM. The pravastatin-induced increase in TM expression in TNFα-treated HAECs was mediated through inhibition of NF-κB activation. Pravastatin regulates TM expression by inhibiting the activation of the Rho family proteins, Rac1 and Cdc42, and the transcription factor, NF-κB. The increase in endothelial TM activity in response to pravastatin constitutes a novel pleiotropic (nonlipid-related) effect of this commonly used compound and may be of clinical significance in disorders in which deficient endothelial TM plays a pathophysiological role.
| Original language | English |
|---|---|
| Pages (from-to) | 642-653 |
| Number of pages | 12 |
| Journal | Journal of Cellular Biochemistry |
| Volume | 101 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Jun 1 2007 |
| Externally published | Yes |
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Keywords
- Endothelial cells
- NF-κB
- Pravastatin
- Rac1/Cdc42
- Thrombomodulin
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
Cite this
Pravastatin induces thrombomodulin expression in TNFα-treated human aortic endothelial cells by inhibiting Rac1 and Cdc42 translocation and activity. / Lin, Shing Jong; Chen, Yung Hsiang; Lin, Feng Yen; Hsieh, Li Yuan; Wang, Shu Huei; Lin, Chia Ying; Wang, Yu Chieh; Ku, Hung Hai; Chen, Jaw Wen; Chen, Yuh Lien.
In: Journal of Cellular Biochemistry, Vol. 101, No. 3, 01.06.2007, p. 642-653.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pravastatin induces thrombomodulin expression in TNFα-treated human aortic endothelial cells by inhibiting Rac1 and Cdc42 translocation and activity
AU - Lin, Shing Jong
AU - Chen, Yung Hsiang
AU - Lin, Feng Yen
AU - Hsieh, Li Yuan
AU - Wang, Shu Huei
AU - Lin, Chia Ying
AU - Wang, Yu Chieh
AU - Ku, Hung Hai
AU - Chen, Jaw Wen
AU - Chen, Yuh Lien
PY - 2007/6/1
Y1 - 2007/6/1
N2 - Expression of functionally active thrombomodulin (TM) on the luminal surface of endothelial cells is critical for vascular thromboresistance. The 3-hydroxyl-3-methyl coenzyme A reductase inhibitor, pravastatin, can protect the vasculature in a manner that is independent of its lipid-lowering activity. We examined the effect of pravastatin on TM expression by human aortic endothelial cells (HAECs) with subsequent tumor necrosis factor α (TNFα) stimulation and investigated the signaling pathways involved. TNFα treatment attenuated TM expression in HAECs in a time-dependent manner. Pravastatin upregulated TM levels in TNFα-treated HAECs. Specific inhibition of geranylgeranyl-transferase-I or the Rho family by GGTI-286 or TcdB, respectively, enhanced TM expression in TNFα-treated HAECs, whereas MAP kinase inhibitors, inactivation of Rho by Clostridium botulinum C3 exoenzyme, or the Rho kinase inhibitor, Y-27632, had no effect. In TNFα-treated HAECs, pravastatin inhibited Rac1 and Cdc42 activation and their translocation to the cell membrane. Blocking the transcriptional activation of NF-κB prevented the TNFα-induced downregulation of TM. The pravastatin-induced increase in TM expression in TNFα-treated HAECs was mediated through inhibition of NF-κB activation. Pravastatin regulates TM expression by inhibiting the activation of the Rho family proteins, Rac1 and Cdc42, and the transcription factor, NF-κB. The increase in endothelial TM activity in response to pravastatin constitutes a novel pleiotropic (nonlipid-related) effect of this commonly used compound and may be of clinical significance in disorders in which deficient endothelial TM plays a pathophysiological role.
AB - Expression of functionally active thrombomodulin (TM) on the luminal surface of endothelial cells is critical for vascular thromboresistance. The 3-hydroxyl-3-methyl coenzyme A reductase inhibitor, pravastatin, can protect the vasculature in a manner that is independent of its lipid-lowering activity. We examined the effect of pravastatin on TM expression by human aortic endothelial cells (HAECs) with subsequent tumor necrosis factor α (TNFα) stimulation and investigated the signaling pathways involved. TNFα treatment attenuated TM expression in HAECs in a time-dependent manner. Pravastatin upregulated TM levels in TNFα-treated HAECs. Specific inhibition of geranylgeranyl-transferase-I or the Rho family by GGTI-286 or TcdB, respectively, enhanced TM expression in TNFα-treated HAECs, whereas MAP kinase inhibitors, inactivation of Rho by Clostridium botulinum C3 exoenzyme, or the Rho kinase inhibitor, Y-27632, had no effect. In TNFα-treated HAECs, pravastatin inhibited Rac1 and Cdc42 activation and their translocation to the cell membrane. Blocking the transcriptional activation of NF-κB prevented the TNFα-induced downregulation of TM. The pravastatin-induced increase in TM expression in TNFα-treated HAECs was mediated through inhibition of NF-κB activation. Pravastatin regulates TM expression by inhibiting the activation of the Rho family proteins, Rac1 and Cdc42, and the transcription factor, NF-κB. The increase in endothelial TM activity in response to pravastatin constitutes a novel pleiotropic (nonlipid-related) effect of this commonly used compound and may be of clinical significance in disorders in which deficient endothelial TM plays a pathophysiological role.
KW - Endothelial cells
KW - NF-κB
KW - Pravastatin
KW - Rac1/Cdc42
KW - Thrombomodulin
UR - http://www.scopus.com/inward/record.url?scp=34247857446&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247857446&partnerID=8YFLogxK
U2 - 10.1002/jcb.21206
DO - 10.1002/jcb.21206
M3 - Article
VL - 101
SP - 642
EP - 653
JO - Journal of Cellular Biochemistry
JF - Journal of Cellular Biochemistry
SN - 0730-2312
IS - 3
ER -