Journal
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
Volume 59, Issue 2, Pages 165-174Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FJC.0b013e31823a39c7
Keywords
everolimus; vascular smooth muscle; proliferation; migration; drug-eluting stent; cell signaling
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Everolimus, a pharmaceutical component of drug-eluting stents, inhibits coronary vessel restenosis, but the anti-restenotic 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 mu M. 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 anti-proliferative, 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.
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