Objects As we studied before, rapamycin released from drug-eluting stents (DESs) affected the antithrombogenic function of endothelial cells through Krüppel-Like Factor 2 (KLF2) decrease. However, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to modulate endothelial function by inducing KLF2. Here we report that statin-induced expression of KLF2 can reverse stent thrombosis.
Methods We observed the effect of rapamycin on expression of KLF2, endothelial NO synthase (eNOS), tissue-plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1) and tissue factor (TF) in Human Umbilical Vein Endothelial Cells (HUVECs). And then KLF2 mRNA was induced by treatment with multiple statins in a concentration-dependent manner. The mRNA and protein were mensurated by RT-PCR and Western Blot Analysis. Furthermore, activation of KLF2 was evaluated by Electrophoretic Mobility Shift Assay (EMSA).
Results Rapamycin made the expression and activation of KLF2 strongly reduce by 75.6% and 78.2% so as to induce long-term coronary endothelial dysfunction. In HUVECs, rapamycin made basal eNOS and t-PA decrease by 80% and 87.8%, while making basal PAI-1 and TF increase by 2.5 and 1.5-fold. After treatment by statins (especially lovastatin), the expression of KLF2 was increased by 3.8-fold nearly reversing to normal state.
Conclusions Taken together, these observations indicate that statin-dependent induction of KLF2 provides a new treatment for stent thrombosis induced by rapamycin releasing from drug-eluting stents.
- signal transduction
- myocardial infarction
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