Rapamycin, but not FK-506, increases endothelial tissue factor expression - Implications for drug-eluting stent design

Article

关键词: ACUTE MYOCARDIAL-INFARCTION;    SMOOTH-MUSCLE-CELLS;    CORONARY-ARTERY;    BALLOON INJURY;    KINASE;    IMPLANTATION;    ANGIOPLASTY;    INHIBITION;    PHOSPHORYLATION;    RESTENOSIS;   

DOI  :  10.1161/CIRCULATIONAHA.105.569129

来源: SCIE

【 摘 要 】

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)-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may be clinically relevant for patients receiving drug-eluting stents, particularly when antithrombotic drugs are withdrawn or ineffective, and may open novel perspectives for the design of such stents.

【 授权许可】

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