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Endothelial Cell Senescence with Age is Associated with Oxidative Stress‐Mediated Suppression of Endothelial Function in Healthy Adults
Author(s) -
Hill S,
McNamara M,
Seals D,
Kaplon R
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb572
Subject(s) - senescence , oxidative stress , medicine , endocrinology , nitrotyrosine , endothelial dysfunction , endothelial stem cell , nadph oxidase , chemistry , nitric oxide , nitric oxide synthase , biochemistry , in vitro
Senescence is emerging as a key mechanism of vascular aging, but evidence in healthy humans is lacking. We hypothesized that endothelial cells (EC) become senescent with age in healthy adults and that this is associated with endothelial dysfunction. In biopsied venous EC, expression of the cell cycle inhibitors p16 and p21 was greater in middle‐aged and older (MA/O, n=10, 60±1 yr) vs. young (Y, n=9, 22±1 yr) healthy adults (p16: 0.45±0.04 vs. 0.28±0.03 AU, P<0.01; p21: 0.63±0.06 vs. 0.34±0.03 AU, P<0.01; quantitative immunofluorescence) whereas p53 did not reach significance (P>0.05). Similarly, EC expression of p16, p21, and p53 was positively related to age (p16: r=0.65, p<0.01; p21: r=0.72, P<0.01; p53: r=0.42, P<0.01). Flow‐mediated dilation (FMD), a measure of endothelial function, was 47% lower in MA/O vs. Y (4.7±0.6 vs. 8.9±0.9%, P<0.01) and was inversely related to EC p21 expression (r=‐0.43, P<0.05). MA/O also had elevated EC abundance of nitrotyrosine (NT), a marker of oxidative protein damage, compared with Y (0.53±0.05 vs. 0.33±0.04 AU, P<0.01) and greater expression of the pro‐oxidant enzyme NADPH oxidase (‐0.28±0.11 vs. ‐0.57±0.08 log(AU), P<0.05). Oxidative stress‐mediated suppression of endothelial function, as indicated in the percent change in FMD following intravenous vitamin C (FMDvc), was greater in MA/O vs. Y (38±17 vs. ‐2±6 %Δ, P<0.05). FMDvc was positively related to EC expression of p16, p21, and p53 (p16: r=0.63, P<0.01; p21: r=0.46, P=0.05; p53: r=0.58, P<0.05). These findings provide novel evidence that senescence occurs in human EC with age in healthy adults and is associated with oxidative stress‐mediated suppression of endothelial function. NIH AG044031 TR001082 AG013038