Nuclear Factor-κΒ–Mediated Regulation of Telomerase

Abstract

Vascular injury induces vascular smooth muscle cell (VSMC) migration, proliferation, and synthesis of extracellular matrix; together with resolution of thrombus, the new tissue formed results in neointima formation, which can result in angioplasty or stent stenosis.1 VSMC proliferation is seen as key to neointima formation, and numerous antiproliferative compounds have been used clinically to prevent neointima formation. Animal studies have also shown that suppression of the early gene response after injury (eg, by suppression of the proto-oncogenes c- myc 2 and c- myb 3) reduces neointima formation. The stimuli that promote cell proliferation are well established—what is less known is why cells stop proliferating. See accompanying article on page 2604 Senescence describes the process of irreversible withdrawal from the cell cycle, with cells unable to reenter even with mitogenic stimulation. Telomeres are tandem repeats of DNA sequences that form the end of chromosomes and prevent chromosome fusion or end joining. Most untransformed cells undergo telomere shortening with each replication, resulting in telomere dysfunction and a DNA damage response that results in irreversible growth arrest or replicative senescence. Senescence can also be triggered by stressors, such as radiation or oxidative species, resulting in stress-induced premature senescence; stress-induced premature senescence is generally not associated with shortened telomeres but is associated with DNA damage. Both replicative senescence with shortened telomeres and stress-induced premature senescence occur in human vascular cells in vitro and in disease …