title: Antirestenotic mechanisms of everolimus on human coronary artery smooth muscle cells: inhibition of human coronary artery smooth muscle cell proliferation, but not migration.
abstract: Everolimus, a pharmaceutical component of drug-eluting stents, inhibits coronary vessel restenosis, but the antirestenotic mechanisms of action remain unclear. Here, we describe the effects of everolimus on key contributors to vessel restenosis, smooth muscle cell proliferation, and migration. In a dose-dependent fashion, everolimus reduced human coronary artery smooth muscle cell (HCASMC) proliferation without toxicity in a bimodal fashion, with accentuated potency occurring at 10 μM. Everolimus arrested the majority of HCASMCs in G1-phase, whereas it reduced the fraction of cells in S-phase at doses that inhibited DNA synthesis (bromodeoxyuridine incorporation). Consistent with this, Western blotting demonstrated that everolimus reduced activation and expression of G1-phase cell cycle progression factors, including p70S6K and cyclin D, respectively, decreased levels of proliferating cell nuclear antigen, and attenuated growth factor/serum-induced phosphorylation of the cell cycle phase transition intermediate, retinoblastoma protein. Everolimus did not, however, affect HCASMC migration. These observations suggest that everolimus acts as an antiproliferative, but not antimigratory, compound to account for at least some of the clinical efficacy exhibited by this drug as an antirestenotic agent. Moreover, everolimus-induced inhibition of the mammalian target of rapamycin complex 1 and regulation of cyclin-mediated cell cycle progression actions likely account for the antiproliferative effects of this compound on HCASMCs.
authors: Pre-Clinical Cell Biology, Boston Scientific Corporation, Natick, MA 01760, USA.
authors: Mark C
authors: MC
authors: Lavigne
authors: Jessica L
authors: JL
authors: Grimsby
authors: Michael J
authors: MJ
authors: Eppihimer
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000517:prevention & control*; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D056741:Cyclin D / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D056741:Cyclin D; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D011506:Proteins; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus