Nuclear factor {kappa}B-mediated transactivation of telomerase prevents intimal smooth muscle cell from replicative senescence during vascular repair.
OBJECTIVE
To gain insights into mechanisms by which intimal hyperplasia interferes with the repair process by investigating expression and function of the catalytic telomerase reverse transcriptase (TERT) subunit after vascular injury.


RESULTS
Functional telomerase is essential to the replicative longevity of vascular cells. We found that TERT was de novo activated in the intima of injured arteries, involving activation of the nuclear factor 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 because mutation of the E-box in the promoter or overexpression of mitotic arrest deficient 1 (MAD1), a c-Myc competitor, abrogated the transcriptional activity. Inhibition of nuclear factor κB in both intimal SMCs and 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 after vascular injury.


CONCLUSIONS
These results support a model in which vascular injury induces de novo expression of TERT in intimal SMCs via activation of nuclear factor κB and upregulation of c-Myc. The resumed TERT activity is critical for intimal hyperplasia.
Bu
De-xiu
DX
Cardiovascular Research Unit, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden. dbu@rics.bwh.harvard.edu
Johansson
Maria E
ME
Ren
Jingyi
J
Xu
Da-wei
DW
Johnson
F Brad
FB
Edfeldt
Kristina
K
Yan
Zhong-qun
ZQ
D062365:Aminobenzoates / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006965:Hyperplasia; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012313:RNA / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology
D062365:Aminobenzoates; C458523:BIBR 1532; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009281:Naphthalenes; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C422952:telomerase RNA; D016222:Fibroblast Growth Factor 2; D012313:RNA; D051550:I-kappa B Kinase; D019098:Telomerase; C509187:Tert protein, mouse