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• W2024572818 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 geranylgeranyltransferase-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. J. Cell. Biochem. 101: 642–653, 2007. © 2007 Wiley-Liss, Inc." @default.
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• W2024572818 date "2007-01-01" @default.
• W2024572818 modified "2023-09-25" @default.
• W2024572818 title "Pravastatin induces thrombomodulin expression in TNFα-treated human aortic endothelial cells by inhibiting Rac1 and Cdc42 translocation and activity" @default.
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• W2024572818 doi "https://doi.org/10.1002/jcb.21206" @default.
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