Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing.
Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing.
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依维莫司的端粒酶抑制作用通过表观遗传基因沉默来抑制平滑肌细胞增殖和新内膜形成。
DOI：
10.1016/j.jacbts.2016.01.002
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Bruemmer,Dennis
中科院分区：
文献类型：
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作者：
Aono,Jun;Ruiz-Rodriguez,Ernesto;Qing,Hua;Findeisen,HannesM;Jones,KarrieL;Heywood,ElizabethB;Bruemmer,Dennis
药物洗脱支架可防止新生内膜形成过程中的平滑肌细胞(SMCs)增殖。端粒酶的表达增强了哺乳动物细胞的复制能力；然而，端粒酶在新生内膜形成的增殖反应中的作用及其作为药物靶点的潜在作用尚不清楚。本研究探讨了端粒酶促有丝分裂功能的机制，并验证了药物洗脱支架常用的伊波莫司通过靶向端粒酶抑制SMC增殖的假说。在过度表达端粒酶逆转录酶(TERT)的小鼠中，伊波利莫斯对新生内膜形成的抑制作用消失，表明抑制端粒酶赋予了伊波利莫斯的抗增殖作用。依维莫司通过抑制Ets-1依赖的启动子激活来减少SMC中TERT的表达。依维莫司抑制TERT依赖性的SMC增殖是在没有端粒缩短的情况下发生的，而是通过→-G1期的S期阻滞来实现的。虽然依维莫司作为S期进入的守门人，未能抑制视网膜母细胞瘤蛋白的磷酸化，但它有效地抑制了下游靶基因的表达。染色质免疫沉淀分析表明，端粒酶逆转录酶诱导E2F与S期基因启动子结合，并支持组蛋白乙酰化。这些效应对伊维洛莫司的抑制作用敏感。这些结果表明，端粒酶是伊维洛莫司抗增殖活性的一个未知靶点，并进一步确定了一种新的有丝分裂途径，该途径依赖于端粒酶逆转录酶对S期基因启动子的表观遗传激活。
Proliferation of smooth muscle cells (SMCs) during neointima formation is prevented by drug-eluting stents. The replicative capacity of mammalian cells is enhanced by telomerase expression; however, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target are unknown. The present study investigated the mechanisms underlying the mitogenic function of telomerase, and tested the hypothesis that everolimus, which is commonly used on drug-eluting stents, suppresses SMC proliferation by targeting telomerase. Inhibition of neointima formation by everolimus was lost in mice overexpressing telomerase reverse transcriptase (TERT), indicating that repression of telomerase confers the anti-proliferative efficacy of everolimus. Everolimus reduced TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S-phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Chromatin immunoprecipitation assays demonstrated that TERT induced E2F binding to S-phase gene promoters and supported histone acetylation. These effects were sensitive to inhibition by everolimus. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus, and further identify a novel mitogenic pathway in SMC that depends on the epigenetic activation of S-phase gene promoters by TERT.