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(Circulation Research. 2004;94:918.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Reconstituted High-Density Lipoprotein Inhibits Thrombin-Induced Endothelial Tissue Factor Expression Through Inhibition of RhoA and Stimulation of Phosphatidylinositol 3-Kinase but not Akt/Endothelial Nitric Oxide Synthase

Hema Viswambharan, Xiu-Fen Ming, Shengsi Zhu, Alphonse Hubsch, Peter Lerch, Guy Vergères, Sandro Rusconi, Zhihong Yang

From the Department of Medicine, Divisions of Physiology (H.V., X.-F.M., S.Z., Z.Y.) and Biochemistry (S.R.), University of Fribourg, Fribourg, Switzerland; and ZLB Bioplasma AG (A.H., P.L., G.V.), Bern, Switzerland.

Correspondence to Prof Dr Zhihong Yang, Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, Rue du Musée 5, CH-1700, Fribourg, Switzerland. E-mail Zhihong.Yang{at}unifr.ch

Endothelial cells express negligible amounts of tissue factor (TF) that can be induced by thrombin, which is important for acute coronary syndromes. Recent research suggests that endothelial TF expression is positively regulated by RhoA and p38^mapk, but negatively by Akt/endothelial nitric oxide synthase (eNOS) pathway. High-density lipoprotein (HDL) is atheroprotective and exerts antiatherothrombotic effect. This study investigated the effect of a reconstituted HDL (rHDL) on endothelial TF expression induced by thrombin and the underlying mechanisms. In cultured human umbilical vein and aortic endothelial cells, thrombin (4 U/mL, 4 hours) increased TF protein level, which was reduced by rHDL (0.1 mg/mL, 43% inhibition, n=3 to 7, P<0.01). Activation of RhoA but not p38^mapk by thrombin was prevented by rHDL. rHDL stimulated Akt/eNOS pathway. The phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY294002 abolished the activation of Akt/eNOS and reversed the inhibitory effect of rHDL on TF expression. Adenoviral expression of the active PI3K mutant (p110) reduced TF expression stimulated by thrombin without inhibiting RhoA activation, whereas expression of the active Akt mutant (m/p) further facilitated TF upregulation by thrombin. Moreover, a dominant-negative Akt mutant (KA) reduced thrombin’s effect and did not reverse the rHDL’s inhibitory effect on TF expression. Inhibition of eNOS by N-nitro-L-arginine methyl ester (100 µmol/L) did not affect the rHDL’s effect. In conclusion, rHDL inhibits thrombin-induced human endothelial TF expression through inhibition of RhoA and activation of PI3K but not Akt/eNOS. These findings implicate a novel mechanism of antiatherothrombotic effects of HDL.

Key Words: atherosclerosis • cell culture/isolation • endothelial dysfunction • tissue factor • lipoproteins

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