Visual Abstract - Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing: 10.1016/j.jacbts.2016.01.002
The proliferative capacity of smooth muscle cells (SMC) during neointima formation is prevented by everolimus-coated drug-eluting stents.
Everolimus failed to inhibit neointima formation by in mice overexpressing telomerase reverse transcriptase (TERT).
Everolimus reduced TERT-dependent SMC proliferation through inhibition of Ets-1–dependent promoter activation.
The inhibition of TERT-dependent SMC proliferation by everolimus occurred as a result of a G1→S-phase arrest, rather than telomerase shortening.
Chromatin immunoprecipitation assays demonstrated that TERT induced E2F binding to S-phase gene promoters and supported histone acetylation.
These studies identify a novel mitogenic pathway in SMC that depends on the epigenetic activation of S-phase gene promoters by TERT.