Pitavastatin-induced thrombomodulin expression by endothelial cells acts via inhibition of small G proteins of the Rho family.
OBJECTIVE
3-hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. The main feature of the antithrombotic properties of endothelial cells is an increase in the expression of thrombomodulin (TM) without induction of tissue factor (TF) expression. We investigated the effect of statins on the expression of TM and TF by endothelial cells.


RESULTS
The incubation of endothelial cells with pitavastatin led to a concentration- and time-dependent increase in cellular TM antigen and mRNA levels. In contrast, the expression of TF mRNA was not induced under the same conditions. A nuclear run-on study revealed that pitavastatin accelerates TM transcription rate. The stimulation of TM expression by pitavastatin was prevented by either mevalonate or geranylgeranylpyrophosphate. Specific inhibition of geranylgeranyltransferase-I and Rac/Cdc42 by GGTI-286 and Clostridium sordellii lethal toxin, respectively, enhanced TM expression, whereas inactivation of Rho by Clostridium botulinum C3 exoenzyme was ineffective.


CONCLUSIONS
Statins regulate TM expression via inhibition of small G proteins of the Rho family; Rac/Cdc42. A statin-mediated increase in TM expression by endothelial cells may contribute to the beneficial effects of statins on endothelial function.
Masamura
Katsuhiko
K
Third Department of Internal Medicine, Faculty of Medicine, Fukui Medical University, Matsuoka-cho, Fukui 910-1193, Japan.
Oida
Koji
K
Kanehara
Hideo
H
Suzuki
Jinya
J
Horie
Shuichi
S
Ishii
Hidemi
H
Miyamori
Isamu
I
D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D018180:Thrombomodulin / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism*; D014471:Umbilical Veins; D015854:Up-Regulation
D001426:Bacterial Proteins; D001427:Bacterial Toxins; C437105:GGTI 286; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011804:Quinolines; D012333:RNA, Messenger; D018180:Thrombomodulin; C072292:lethal toxin LT, Clostridium sordellii; C031815:toxB protein, Clostridium difficile; D013925:Thromboplastin; D020559:Monomeric GTP-Binding Proteins; D007930:Leucine; C108475:pitavastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid