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(Circulation. 2005;112:2002-2011.)
© 2005 American Heart Association, Inc.

Interventional Cardiology

Rapamycin, but Not FK-506, Increases Endothelial Tissue Factor Expression

Implications for Drug-Eluting Stent Design

Jan Steffel, MD^*; Roberto A. Latini, MD^*; Alexander Akhmedov, PhD; Dorothee Zimmermann, BSc; Pamela Zimmerling, BSc; Thomas F. Lüscher, MD; Felix C. Tanner, MD

From Cardiovascular Research, Physiology Institute, and the Center for Integrative Human Physiology (J.S., R.A.L., A.A., D.Z., P.Z., T.F.L., F.C.T.), University of Zurich, and the Department of Cardiology (J.S., T.F.L., F.C.T.), Cardiovascular Center, University Hospital Zürich, Zürich, Switzerland.

Correspondence to Felix C. Tanner, MD, Cardiovascular Research, Physiology Institute, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail felix.tanner{at}access.unizh.ch

Received January 7, 2005; de novo received June 15, 2005; accepted July 8, 2005.

Background— Drugs released from stents affect the biology of vascular cells. We examined the effect of rapamycin and FK-506 on tissue factor (TF) expression in human aortic endothelial cells (HAECs) and vascular smooth muscle cells (HAVSMCs).

Methods and Results— Rapamycin enhanced thrombin- and tumor necrosis factor (TNF)-–induced endothelial TF expression in a concentration-dependent manner. The maximal increase was 2.5-fold more pronounced than that by thrombin or TNF- alone and was paralleled by a 1.4-fold higher TF surface activity compared with thrombin alone. Rapamycin by itself increased basal TF levels by 40%. In HAVSMCs, rapamycin did not affect thrombin- or TNF-–induced TF expression. In contrast to rapamycin, FK-506 did not enhance thrombin- or TNF-–induced endothelial TF expression. Thrombin induced a transient dephosphorylation of the mammalian target of rapamycin downstream target p70S6 kinase. Rapamycin completely abrogated p70S6 kinase phosphorylation, but FK-506 did not. FK-506 antagonized the effect of rapamycin on thrombin-induced TF expression. Rapamycin did not alter the pattern of p38, extracellular signal–regulated kinase, or c-Jun NH₂-terminal kinase phosphorylation. Real-time polymerase chain reaction analysis revealed that rapamycin had no influence on thrombin-induced TF mRNA levels for up to 2 hours but led to an additional increase after 3 and 5 hours.

Conclusions— Rapamycin, but not FK-506, enhances TF expression in HAECs but not in HAVSMCs. This effect requires binding to FK binding protein-12, is mediated through inhibition of the mammalian target of rapamycin, and partly occurs at the posttranscriptional level. These findings may be clinically relevant for patients receiving drug-eluting stents, particularly when antithrombotic drugs are withdrawn or ineffective, and may open novel perspectives for the design of such stents.

Key Words: endothelium • myocardial infarction • signal transduction • stents • thrombosis

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