Nuclear factor {kappa}B-mediated transactivation of telomerase prevents intimal smooth muscle cell from replicative senescence during vascular repair.
Nuclear factor {kappa}B-mediated transactivation of telomerase prevents intimal smooth muscle cell from replicative senescence during vascular repair.
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DOI：
10.1161/atvbaha.110.213074
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Yan ZQ
中科院分区：
文献类型：
--
作者：
Bu DX;Johansson ME;Ren J;Xu DW;Johnson FB;Edfeldt K;Yan ZQ
Functional telomerase is essential to the replicative longevity of vascular cells. To gain insights into mechanisms by which intimal hyperplasia interferes with the repair process, expression and function of the telomerase catalytic subunit (TERT) were investigated following vascular injury. We found that TERT was de novo activated in intima of the injured arteries, involving activation of the nuclear factor κB (NF-κB) pathway. Stimulation of the isolated intimal smooth muscle cell (SMC) by basic fibroblast growth factor or tumor necrosis factor α resulted in increased TERT activity. This depends on the activation of c-Myc signaling since mutation of the E-box in the promoter or over-expression of MAD1, a c-Myc competitor, abrogated the transcriptional activity. Inhibition of NF-κB in both intimal SMC and in the injured artery attenuated TERT transcriptional activity through reduction of c-Myc expression. Pharmacological blockade of TERT led to SMC senescence. Finally, depletion of telomerase function in mice resulted in severe intimal SMC senescence following vascular injury. These results support a model whereby vascular injury induces de novo expression of TERT in intimal SMC via activation of NF-κB and up-regulation of c-Myc. The resumed TERT activity is critical for intimal hyperplasia.
