Abstract
Several lines of evidence suggest an inhibitory role of dietary nucleotides (NTs) against oxidative stress and inflammation, which promote senescence in age-associated cardiovascular diseases. We sought to test whether the dietary NTs could retard the hydrogen peroxide (H2O2)-induced senescence of human umbilical vein endothelial cells (HUVECs) and to elucidate the efficiency of different NTs as well as the potential mechanism. Senescence was induced in HUVECs by 4 h exposure to 200 µM H2O2 and was confirmed using senescence-associated-β-galactosidase staining (SA-β-gal), cell viability, and Western blot analyses of p16INK4A and p21Waf1/Cip1 after 24 h administration of growth medium. We find that NTs retards oxidative stress-induced HUVECs senescence, as shown by a lower percentage of SA-β-gal-positive cells, lower expression of p16INK4A, and p21Waf1/Cip1 as well as higher cell viability. GMP100 was the most excellent in delaying HUVECs senescence, which was followed by the NTs mixture, NMN, CMP50, and UMP50/100, while AMP retards HUVECs senescence by specifically reducing p15INK4b expression. NTs all have significant anti-inflammatory effects; AMP and CMP were more prominent in restoring mitochondrial function, GMP and CMP were more competent at eliminating ROS and MDA, while AMP and UMP were more efficient at enhancing antioxidant enzyme activity. The role of the NTs mixture in retarding HUVECs senescence is full-scaled. These results stated that the mechanisms of NTs retarding HUVECs senescence could be related to its antioxidant and anti-inflammation properties promoting cell proliferation and protecting mitochondrial function activities.
Highlights
Cardiovascular diseases (CVDs) are the leading cause of death globally [1], and the strongest independent risk factor for CVDs is age: more than 90% of CVDs occur in adults age 40 and older [2]
Decreased cell viability was observed in senescent human umbilical vein endothelial cells (HUVECs), while the treatment with NTs leads to considerable improvement (Figure 1B)
There was a tendency toward higher expression, the expression of p15INK4b was not significantly altered in senescent HUVECs compared with the control group, and a significantly decreased level of p15INK4b was seen in the AMP50 group compared with the model group (Figure 4H–J)
Summary
Cardiovascular diseases (CVDs) are the leading cause of death globally [1], and the strongest independent risk factor for CVDs is age: more than 90% of CVDs occur in adults age 40 and older [2]. As a hallmark of aging, senescent cells could play a detrimental role in age-associated pathologies [3,4]. The accumulation of senescent cells with age might trigger a chronic inflammation with detrimental effects on neighboring cells and the whole organism, contributing to the initiation and progression of CVDs [11]. There is a large body of evidence that senescent cells are present in the pathological tissues of patients with CVDs [12]. The expression of senescence markers including SA-β-gal, p16INK4A , and p21Waf1/Cip was upregulated in endothelial cells from human atherosclerotic plaques [13]. A treatment that attempts to eliminate p16-positive senescent cells could be used to prevent and treat the CVDs [14,15,16]
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