Pitavastatin-Induced Thrombomodulin Expression by Endothelial Cells Acts Via Inhibition of Small G Proteins of the Rho Family

Abstract

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. Methods and 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. Key Words: endothelium Ⅲ thrombomodulin Ⅲ statins Ⅲ small GTPase V ascular endothelial cells play an active role in the regulation of blood coagulation and fibrinolysis. 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. TM is a high-affinity receptor for thrombin that is present on endothelial cell surfaces. By forming a complex with thrombin, TM alters the procoagulant activity of thrombin and acts as a cofactor for the thrombin-catalyzed activation of circulating protein C. Activated protein C functions as an anticoagulant via the proteolytic degradation of the coagulation factors Va and VIIIa, thereby limiting the generation of thrombin. Thus, the TM-protein C pathway is a major antithrombotic mechanism present in endothelial cells, and TM is important in regulating the fluidity of circulating blood.Tissue factor (TF), a membrane glycoprotein receptor that specifically binds factors VII or VIIa, functions as a cellular trigger of the coagulation cascade via activation of factors X and IX. Under normal circumstances, endothelial cells do not display TF activity. Thus, the normal vascular endothelium is relatively inert with respect to initiation of coagulation. A procedure to enhance upregulation of TM without induction of TF expression in cells provides an important clue toward the therapy and prevention of vascular thrombosis. 1 Activated protein C also functions as an important modulator of inflammation associated with severe sepsis. 2 In vitro data indicate that activated protein C exerts an anti-inflammatory effect by both inhibiting the production of inflammatory cytokines (tumor necrosis factor-␣, interleukin-1, and interleukin-6) by monocytes and limiting the rolling of monocytes and neutrophils on injured endothelium via selectin binding. 3 Activated protein C indirectly increases the fibrinolytic response by inhibiting plasminogen activator inhibitor. Recently, it has been shown that treatment with activated protein C significantly reduced mortality in patients with severe sepsis. 4 Inhibitors of 3-hydroxyl-3-methyl coenzyme A (HMGCoA) reductase (statins) are widely used in the treatment of hypercholesterolem...

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