Rapamycin, but not FK-506, increases endothelial tissue factor expression: implications for drug-eluting stent design.
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).


RESULTS
Rapamycin enhanced thrombin- and tumor necrosis factor (TNF)-alpha-induced endothelial TF expression in a concentration-dependent manner. The maximal increase was 2.5-fold more pronounced than that by thrombin or TNF-alpha 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-alpha-induced TF expression. In contrast to rapamycin, FK-506 did not enhance thrombin- or TNF-alpha-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may be clinically relevant for patients receiving drug-eluting stents, particularly when antithrombotic drugs are withdrawn or ineffective, and may open novel perspectives for the design of such stents.
Steffel
Jan
J
Cardiovascular Research, Physiology Institute, Center for Integrative Human Physiology, University of Zurich, CH-8057 Zürich, Switzerland.
Latini
Roberto A
RA
Akhmedov
Alexander
A
Zimmermann
Dorothee
D
Zimmerling
Pamela
P
Lüscher
Thomas F
TF
Tanner
Felix C
FC
D001011:Aorta; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D004867:Equipment Design; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology*; D015607:Stents; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D013925:Thromboplastin; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus; D016559:Tacrolimus