AIMS: Drug-eluting stents (DES) may be associated with an increased risk for stent thrombosis when compared with bare-metal stents. In endothelial cells, rapamycin induces tissue factor (TF) by inhibiting the mammalian target of rapamycin (mTOR). However, the effect of mTOR inhibition on TF activity and thrombus formation in vivo has not yet been studied. Moreover, it is unclear whether second-generation DES substances everolimus and zotarolimus have an effect on endothelial TF expression. METHODS AND RESULTS: In a mouse carotid artery photochemical injury model, rapamycin (182 +/- 27.5 microg/L) decreased time to thrombotic occlusion by 40%, increased TF activity, and abrogated p70S6K phosphorylation when compared with controls. In vitro, rapamycin, everolimus, and zotarolimus (each 10(-7) mol/l) enhanced TNF-alpha-induced TF expression by 2.2-, 1.7-, and 2.4-fold, respectively, which was paralleled by an increase in TF surface activity. Similar to rapamycin, everolimus and zotarolimus abrogated TNF-alpha-induced p70S6K phosphorylation under these conditions. CONCLUSION: Rapamycin increases TF activity and promotes arterial thrombosis in vivo at concentrations relevant in patients undergoing DES implantation; this effect may increase the thrombogenicity of DES. Since everolimus and zotarolimus augment endothelial TF expression and activity in vitro in a similar manner as rapamycin, these findings may also be relevant for second generation DES.
AIMS: Drug-eluting stents (DES) may be associated with an increased risk for stent thrombosis when compared with bare-metal stents. In endothelial cells, rapamycin induces tissue factor (TF) by inhibiting the mammalian target of rapamycin (mTOR). However, the effect of mTOR inhibition on TF activity and thrombus formation in vivo has not yet been studied. Moreover, it is unclear whether second-generation DES substanceseverolimus and zotarolimus have an effect on endothelial TF expression. METHODS AND RESULTS: In a mouse carotid artery photochemical injury model, rapamycin (182 +/- 27.5 microg/L) decreased time to thrombotic occlusion by 40%, increased TF activity, and abrogated p70S6K phosphorylation when compared with controls. In vitro, rapamycin, everolimus, and zotarolimus (each 10(-7) mol/l) enhanced TNF-alpha-induced TF expression by 2.2-, 1.7-, and 2.4-fold, respectively, which was paralleled by an increase in TF surface activity. Similar to rapamycin, everolimus and zotarolimus abrogated TNF-alpha-induced p70S6K phosphorylation under these conditions. CONCLUSION:Rapamycin increases TF activity and promotes arterial thrombosis in vivo at concentrations relevant in patients undergoing DES implantation; this effect may increase the thrombogenicity of DES. Since everolimus and zotarolimus augment endothelial TF expression and activity in vitro in a similar manner as rapamycin, these findings may also be relevant for second generation DES.
Authors: Nicole C Kleinstreuer; Jian Yang; Ellen L Berg; Thomas B Knudsen; Ann M Richard; Matthew T Martin; David M Reif; Richard S Judson; Mark Polokoff; David J Dix; Robert J Kavlock; Keith A Houck Journal: Nat Biotechnol Date: 2014-05-18 Impact factor: 54.908