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

Abstract

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 NH 2 -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.

DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

“…Findings from the present study reinforce the concept that DMSO is an interesting alternative for the coating of DES where currently employed drugs do not completely address the risks of stent thrombosis [4,5,14,15,17,20,31,34] and, in addition, were shown to induce the expression of TF [29,32,38].…”

“…Even though coronary bare metal stents (BMS) and drug-eluting stent (DES) implantation greatly improved prognosis of ACS patients, acute and sub-acute stent thrombosis still remain a serious concern [4,5,14,15,17,20,31,34]. In line with this, we recently showed that drugs released from DES enhance tissue factor (TF), a key trigger for thrombosis and thus could play a paradoxical role in eliciting stent thrombosis [29,32]. In this context, DMSO could represent an interesting alternative drug which not only inhibits human vascular smooth muscle cell (HVSMC) proliferation, but also prevents TF expression and thrombus formation in vivo [6].…”

Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3-kinase inhibition

“…The inhibitory role of PI3K on TF expression is well documented, as inhibition of these kinases enhances TF protein expression in response to different mediators (17). PI3Ks are divided into three distinct classes based on their primary structure.…”

“…PI3Ks are important negative regulators of TF expression in human endothelial cells (16,17); and this pathway suppresses inflammation and coagulation in endotoxaemic mice (18). Targeting PI3K activity in various inflammatory conditions has become an active area of investigation (19,20).…”

Antiproliferative Agents Alter Vascular Plasminogen Activator Inhibitor-1 Expression

“…17 Mechanistically, it is plausible to consider the possibility that rapamycin does have prothrombotic potential, and indeed this agent has recently been demonstrated to increase tissue factor expression in cultured endothelial cells. 18 Paclitaxel has also been demonstrated to enhance thrombin-induced tissue factor expression in endothelial cells through activation of a c-Jun kinase in endothelial cells. 19 Although the antiproliferative and antimitotic effects of DES are believed to be responsible for preventing restenosis, the effects of these agents on global endothelial gene expression are not known.…”