Telomere length and replicative aging in human vascular tissues.

Abstract

Because repeated injury of the endothelium and subsequent turnover ofintimal and medial cells have been implicated in atherosclerosis, we examined telomere length, a marker of somatic cell turnover, in cells from these tissues.Telomere lengths were assessed by Southern analysis of terminal restriction fragments (TRFs) generated by Hinfl/Rsa I digestion of human genomic DNA. Mean TRF length decreased as a function of population doublings in human endothelial cell cultures from umbilical veins, iliac arteries, and iliac veins. When endothelial cells were examined for mean TRF length as a function of donor age, there was a significantly greater rate of decrease for cells from iliac arteries than from iliac veins (102 bp/yr vs. 47 bp/yr, respectively, P < 0.05), consistent with higher hemodynamic stress and increased cell turnover in arteries. Moreover, the rate of telomere loss as a function of donor age was greater in the intimal DNA of iliac arteries compared to that of the internal thoracic arteries (147 bp/yr vs. 87 bp/yr, respectively, P < 0.05), a region of the arterial tree subject to less hemodynamic stress. This indicates that the effect is not tissue specifi'c. DNA from the medial tissue of the iliac and internal thoracic arteries showed no significant difference in the rates of decrease, suggesting that chronic stress leading to cellular senescence is more pronounced in the intima than in the media. These observations extend the use of telomere size as a marker for the replicative history of cells and are consistent with a role for focal replicative senescence in cardiovascular diseases.In the United States and Western Europe, atherosclerosis is the principal contributor to mortality from cardiovascular diseases (1). Prominent among the mechanisms proposed to explain the pathogenesis of atherosclerosis is the "responseto-injury" hypothesis (1-4) in which repeated mechanical, hemodynamic, and/or immunological injury to mural and focal regions of the endothelium is the initiating event to vascular dysfunction. Such insults precipitate an inflammatory-fibroproliferative response from the damaged vasculature. The response is characterized by adhesion of platelets and macrophages on the site of injury, the formation of lipid and cell-rich lesions or "plaques" on the intimal or lumenal surfaces of arterial tissues, and the invasion of underlying smooth muscle cells into the intimal space. If left unchecked, there will follow an age-dependent expansion of the lesion into the lumen, potentially leading to occlusion and infarction at myocardial, cerebral, or other sites (5-7).A prediction of this hypothesis is that the intimal and medial tissue in the area comprising the atherosclerotic plaque have augmented cell turnover compared to surrounding normal tissue. There is evidence demonstrating age-dependent turnover of vascular tissue. Bierman (8) showed an inverse correlation between donor age and the replicative potential of human arterial smooth-muscle cell culture. Martin et al. (9) also showed negative...

Telomere Shortening of Peripheral Blood Mononuclear Cells in Coronary Disease Patients with Metabolic Disorders.

“…It is reported that telomere shortening occurs in correlation with cell turnover and aging. In addition, the telomere length of peripheral blood mononuclear cells has been reported to decrease gradually with aging, and change in parallel with that of coronary arterial endothelial cells, which may be prone to more rapid shortening than other endothelial cells because of their high turnover rate due to greater blood turbulence (5,15,16). In spite of the importance of telomere length in cell physiology, its regulation remains largely unknown.…”

Telomerase and the aging process

“…One example is of particular interest: proliferative capacity is closely related to telomere length in endothelial cells. Telomere lengths in endothelial cells decreased as a function of donor age, with a greater decline being observed in cells isolated from the iliac artery in comparison to cells from the thoracic artery (Chang and Harley, 1995). The greater decline in telomere length was observed in the cells had likely undergone more proliferation in vivo, because they resided in a part of the vascular system where blood flow might cause most chronic damage to the endothelium.…”

Endothelial dysfunction and hypertension in aging

“…It is well known that aging and hypertension are associated with shortening of telomeres induced by decrease in TERT activity in endothelial cells. [124][125][126] However, unfortunately, it remains unclear whether telomere shortening is a cause or consequence of aging.…”