Metformin Impairs Vascular Endothelial Recovery After Stent Placement in the Setting of Locally Eluted Mammalian Target of Rapamycin Inhibitors Via S6 Kinase-Dependent Inhibition of Cell Proliferation

• Published in: Journal of the American College of Cardiology Vol. 61; no. 9; pp. 971 - 980
• Main Authors: Habib, Anwer, MD, Karmali, Vinit, MA, Polavarapu, Rohini, BA, Akahori, Hirokuni, MD, PhD, Nakano, Masataka, MD, Yazdani, Saami, PhD, Otsuka, Fumiyuki, MD, Pachura, Kim, BS, Davis, Talina, Narula, Jagat, MD, PhD, Kolodgie, Frank D., PhD, Virmani, Renu, MD, Finn, Aloke V., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 05.03.2013; Elsevier; Elsevier Limited
• Subjects: Administration, Oral; Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Aorta - cytology; Apoptosis; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiovascular; Cardiovascular disease; Cell growth; cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Diabetes; Drug Interactions; Drug-Eluting Stents; Endothelial Cells - cytology; Endothelial Cells - drug effects; endothelium; Endothelium, Vascular - cytology; Heart; Humans; Iliac Artery; Insulin; Internal Medicine; Kinases; Medical sciences; metformin; Metformin - administration & dosage; Metformin - adverse effects; Microscopy, Electron, Scanning; Pharmacology. Drug treatments; Phosphorylation; Rabbits; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Ribosomal Protein S6 Kinases - antagonists & inhibitors; Ribosomal Protein S6 Kinases - physiology; S6K; Scanning electron microscopy; Sirolimus - analogs & derivatives; Sirolimus - antagonists & inhibitors; Sirolimus - pharmacology; Statistical analysis; Stents; Studies; Thrombosis; platelet endothelial cell adhesion molecule 1; ZES; human aortic endothelial cell; zotarolimus-eluting stent(s); short interfering RNA; SRL; drug-eluting stent(s); everolimus; mammalian target of rapamycin; shRNA; short hairpin RNA; sirolimus; eIF4E binding protein; mTOR; mammalian target of rapamycin complex 1; endothelium; bare-metal stent(s); drug-eluting stents; cell proliferation; 5'-adenosine monophosphate–activated protein kinase; S6 kinase; metformin; S6K; BMS; 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 3′,5′ cyclic monophosphate; siRNA; DES; 4E-BP; HAEC; PECAM1; AMPK; Mf; AICAR; EVL; mTORC1; Antineoplastic agent; Cell proliferation; Sirolimus; Cardiovascular disease; Health service; Recovery; Stent; Macrocycle; Target; Hypoglycemic agent; Biguanides; Blood vessel; Protein synthesis inhibitor; Inhibition; Cardiology; Endoprosthesis; Enzyme; Transferases; Setting; Instrumentation therapy; Lactone; Macrolide; Endothelium; Vertebrata; Antibiotic; Mammalia; Kinase; Circulatory system; Immunosuppressive agent; Metformin; Antibacterial agent
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2012.12.018

Objectives This study sought to examine the effect of oral metformin (Mf) therapy on endothelialization in the setting of drug-eluting stents (DES). Background Mf is a commonly used therapy in diabetic patients receiving DES. Mf and locally eluted mammalian target of rapamycin (mTOR) inhibitors used in DES have convergent molecular signaling; however, the impact of this drug interaction on stent endothelialization is unknown. Methods We examined human endothelial aortic cells (HAECs) and a rabbit model of stenting to determine points on molecular convergence between these 2 agents and their impact on stent endothelialization. Results Western blotting of HAECs treated with Mf and the mTOR inhibitor sirolimus and 14-day rabbit iliacs treated with the combination of zotarolimus-eluting stents (ZES) and oral Mf 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 sirolimus treatments alone and further reduced when they were combined. Knockdown of S6K via short interfering RNA in HAECs impaired cell proliferation via a cyclin D1–dependent mechanism, whereas its overexpression rescued the antiproliferative effects of both agents. Last, endothelialization and endothelial cell proliferation at 14 days were assessed in rabbits receiving ZES or bare-metal stents and Mf or placebo by scanning electron microscopy and bromodeoxyuridine/CD31 labeling, respectively. Both endpoints were inhibited by ZES treatment alone and were further reduced by the combination of Mf and ZES. Conclusions Significant convergence of signaling occurs between Mf and locally delivered mTOR inhibitors at S6K. This further impairs endothelial recovery/proliferation via an S6K-dependent mechanism. Patients receiving Mf in combination with stents that elute mTOR inhibitors are potentially at increased risk of delayed endothelial healing and stent thrombosis.