Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 30, Issue 12, Pages 2604-2610Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.110.213074
Keywords
telomerase; nuclear factor-kappa B; smooth muscle cell; intimal hyperplasia; gene expression; gene therapy; genetically altered mice; molecular biology; vascular biology
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Funding
- Swedish Research Council [2004-3469, 2007-3337]
- Swedish Research Link [2005-6333]
- Swedish Heart-Lung Foundation [20080844]
- European Unin (Immunath, AtheroRemo) [2006-037400, 201668]
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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. Methods and 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 kappa B pathway. Stimulation of the isolated intimal smooth muscle cell (SMC) by basic fibroblast growth factor or tumor necrosis factor alpha 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 kappa B 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. Conclusion-These results support a model in which vascular injury induces de novo expression of TERT in intimal SMCs via activation of nuclear factor kappa B and upregulation of c-Myc. The resumed TERT activity is critical for intimal hyperplasia. (Arterioscler Thromb Vasc Biol. 2010;30:2604-2610.)
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