Abstract 10777: Metformin Impairs Vascular Endothelial Recovery After Stent Placement In the Setting of Locally Eluted mTOR inhibitors via S6K Dependent Inhibition of Cell Proliferation
Introduction: Treatment of diabetic patients with coronary artery disease involve medical therapy and coronary intervention with drug eluting stents (DES) most of which elute mechanistic target of rapamycin (mTOR) inhibitors. Convergence of molecular signaling between systemic medications and locally eluted mTOR inhibitors may affect vascular repair through modulation of mTOR signaling however its impact on endothelialization is unknown.
Hypothesis: We hypothesize that Metformin (Mf), a common anti-diabetic medication with effects on mTOR signaling, will further impact endothelialization in the setting of DES.
Methods and Results: Immunoblotting of human aortic endothelial cells (HAEC) treated with Mf and the mTOR inhibitor sirolimus (SRL) and 14 day rabbit iliacs treated with zotarolimus eluting stents (ZES) and oral Mf (100mg/kg/day) both demonstrated greater inhibition of S6 Kinase (S6K), a downstream effector of mTOR Complex 1, than either treatment alone. HAEC proliferation was significantly inhibited by Mf or SRL treatments and further reduced when they were combined. Knockdown of S6K via siRNA in HAECs impaired cell proliferation via a cyclin D1 dependent mechanism while its overexpression rescued the anti-proliferative effects of both agents. Lastly, endothelialization and endothelial proliferation at 14 days were assessed in rabbits receiving ZES or bare metal stents (BMS) and Mf or placebo by scanning electron microscopy and ratio of BrdU / CD31 labeling (figure), respectively. Both endpoints were inhibited by Mf or ZES treatments alone and further reduced by the combination of Mf and ZES.
Conclusions: Significant convergence of signaling occurs between Mf and locally delivered mTOR inhibitors at S6K; further impairing endothelial proliferation via a S6K dependent mechanism. Patients receiving Mf in combination with stents that elute mTOR inhibitors are potentially at increased risk for delayed endothelial healing and stent thrombosis.
- © 2012 by American Heart Association, Inc.