Pravastatin induces thrombomodulin expression in TNFalpha-treated human aortic endothelial cells by inhibiting Rac1 and Cdc42 translocation and activity.
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 alpha (TNFalpha) stimulation and investigated the signaling pathways involved. TNFalpha treatment attenuated TM expression in HAECs in a time-dependent manner. Pravastatin upregulated TM levels in TNFalpha-treated HAECs. Specific inhibition of geranylgeranyltransferase-I or the Rho family by GGTI-286 or TcdB, respectively, enhanced TM expression in TNFalpha-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 TNFalpha-treated HAECs, pravastatin inhibited Rac1 and Cdc42 activation and their translocation to the cell membrane. Blocking the transcriptional activation of NF-kappaB prevented the TNFalpha-induced downregulation of TM. The pravastatin-induced increase in TM expression in TNFalpha-treated HAECs was mediated through inhibition of NF-kappaB activation. Pravastatin regulates TM expression by inhibiting the activation of the Rho family proteins, Rac1 and Cdc42, and the transcription factor, NF-kappaB. 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.
Lin
Shing-Jong
SJ
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Chen
Yung-Hsiang
YH
Lin
Feng-Yen
FY
Hsieh
Li-Yuan
LY
Wang
Shu-Huei
SH
Lin
Chia-Ying
CY
Wang
Yu-Chieh
YC
Ku
Hung-Hai
HH
Chen
Jaw-Wen
JW
Chen
Yuh-Lien
YL
D000577:Amides / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001896:Boron Compounds / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D018180:Thrombomodulin / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D000577:Amides; D000873:Anthracenes; D001896:Boron Compounds; D005419:Flavonoids; C437105:GGTI 286; D007093:Imidazoles; D011725:Pyridines; C107953:RAC1 protein, human; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; C057908:trimethylaminocarboxyldihydroboran; C108830:Y 27632; C432165:pyrazolanthrone; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D007930:Leucine; D017035:Pravastatin; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one