Nitric oxide activates telomerase and delays endothelial cell senescence.

Abstract

Endothelial cells (ECs) undergo a limited number of cell divisions, ultimately stop dividing, and enter a state that is designated replicative senescence. Shortening of telomeres is believed to be a molecular clock that triggers senescence. Telomerase, a RNA-directed DNA polymerase, extends telomeres of eukaryotic chromosomes and delays the development of senescence. In this study, we examined telomere length and the activity of telomerase during aging of human ECs in culture and elucidated the effect of nitric oxide (NO). A significant increase in senescent cells as detected by acidic β-galactosidase expression and a reduction of telomere length were found after 11 passages. Telomerase activity was reduced after the seventh passage, thereby preceding the development of EC senescence. The repeated addition of the NO donor S -nitroso-penicillamine significantly reduced EC senescence and delayed age-dependent inhibition of telomerase activity, whereas inhibition of endogenous NO synthesis had an adverse effect. Taken together, our results demonstrate that telomerase inactivation precedes EC aging. NO prevents age-related downregulation of telomerase activity and delays EC senescence. The incidence of atherosclerosis increases with age. Aging is associated not only with endothelial dysfunction, a key pathogenic factor in atherosclerotic disease progression,1 2 but also impairs angiogenesis,3 suggesting that the process of aging itself affects endothelial cell (EC) function. On a cellular level, aging leads to an irreversible state of cell cycle arrest known as replicative senescence.4 It is generally believed that a relevant factor in regulating cellular life span is the telomere length.5 Telomerase, a ribonucleoprotein with reverse transcriptase activity, synthesizes the telomeric repeats at the linear ends of eukaryotic chromosomes.5 Telomerase is active in germline cells and cancer cells, whereas it is repressed in most somatic cells, resulting in the progressive telomere shortening with each cell division.6 A recent study demonstrated that homocysteine, …