Senescence-Induced Oxidative Stress Causes Endothelial Dysfunction

Bhayadia, Raj; Schmidt, Bernhard M.W.; Melk, Anette; Hömme, Meike

doi:10.1093/gerona/glv008

Cited by 99 publications

(69 citation statements)

References 57 publications

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“…Therefore, it may have value as a biomarker, but it is difficult to conclude that shorter telomeres in leukocytes directly contribute to vascular aging or CVD. Still, in mice, the accumulation of critically short telomeres in vascular tissue resulting from telomerase deficiency is sufficient to induce endothelial dysfunction, whereas ectopic expression of telomerase in human VSMCs both lengthens telomeres and increases plaque stability via greater cap stability and a normalized VSMC phenotype in atherosclerosis . Still, TERT not only extends the telomere, but also regulates eNOS expression in human microvessels at translational and posttranslational levels as well as prevents oxidative stress via reduced mitochondrial ROS and improved endothelial function .…”

Section: Telomere Dysfunction: An Initial Step For Vascular Agingmentioning

confidence: 99%

The role of senescence, telomere dysfunction and shelterin in vascular aging

2018

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In the United States and other westernized nations, CVDs are the leading cause of death in adults over 65 years of age. Large artery stiffness and endothelial dysfunction are increased with age and age-associated arterial dysfunction is an important antecedent of CVDs. One age-associated change that may contribute to vascular dysfunction and CVD risk is an increase in the number of resident senescent cells in the vasculature. Senescent cells display a pro-oxidant, pro-inflammatory phenotype known as the SASP. However, the mechanisms that drive the SASP and the vascular aging phenotype remain elusive. A putative mechanism is the involvement of oxidative stress and inflammation in telomere function. Telomeres are the end caps of chromosomes which are maintained by a six-protein complex known as shelterin. Disruption of shelterin can uncap telomeres and induce cellular senescence. Accordingly, in this review, we propose that oxidative stress and inflammation disrupt shelterin in vascular cells, driving telomere dysfunction and that this mechanism may be responsible for the induction of SASP. The proposed mechanisms may represent some of the initial changes that lead to vascular dysfunction in advanced age.

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Section: Telomere Dysfunction: An Initial Step For Vascular Agingmentioning

confidence: 99%

The role of senescence, telomere dysfunction and shelterin in vascular aging

2018

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“…Atrial endothelial senescence was found to promote thrombus formation and extracellular matrix remodeling (3). In an aging mouse model with vascular endothelium damage, antioxidant therapy can alleviated the dysfunction of aging vascular endothelium cells (4). Studies have shown that long-term addition of the antioxidant vitamin C (VC), which can reduce the immune levels associated with thymic aging (5).…”

Section: Introductionmentioning

confidence: 99%

Piwi-interacting RNAs play a role in vitamin C-mediated effects on endothelial aging

Zheng

Huang

et al. 2020

Int. J. Med. Sci.

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The underlying mechanisms that mediate the effects of vitamin C on endothelial cell aging are widely unknown. To investigate whether Piwi-interacting RNAs (piRNAs) are involved in this process, an endothelial aging model was induced in vitro using H2O2 in human umbilical vein endothelial cells (HUVECs) and then treated with vitamin C (VC). Untreated HUVECs without H2O2 exposure were used to serve as the negative control group. Cell cycle, cell viability, and aging-associated protein expression were assessed, and RNA sequencing was performed to reveal the piRNA profile. Functional and regulatory networks of the different piRNA target genes were predicted by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis. H2O2 induced G1 phase cell arrest, decreased cell viability, and upregulated the senescence marker p16 in HUVECs. We found that VC treatment inhibited G1 phase cell arrest, increased the number of cells in the S and G2/M phases, increased cell viability, and decreased p16 expression. The piRNA expression profiles revealed that a large proportion of piRNAs that were differentially expressed in H2O2-treated HUVECs were partly normalized by VC. Furthermore, a number of piRNAs associated with the response to VC in H2O2-treated HUVECs were linked with senescence and cell cycle-related pathways and networks. These results indicate that the ability of VC to attenuate H2O2-mediated endothelial cell senescence may be associated with changes in expression of piRNAs that are linked to the cell cycle.

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“…Moreover, cellular senescence is characterized by shortened telomere length or reduced telomerase activity . Oxidative stress and inflammation have been implicated in the ageing process and adversely affect endothelial availability and function . Oxidative stress compromises telomere integrity and nitric oxide (NO) bioavailability to accelerate cellular senescence in endothelial cells .…”

Section: Introductionmentioning

confidence: 99%

Kallistatin attenuates endothelial senescence by modulating Let‐7g‐mediated miR‐34a‐SIRT1‐eNOS pathway

Guo

Chao

2018

J Cellular Molecular Medi

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Kallistatin, a plasma protein, protects against vascular and organ injury. This study is aimed to investigate the role and mechanism of kallistatin in endothelial senescence. Kallistatin inhibited H2O2‐induced senescence in human endothelial cells, as indicated by reduced senescence‐associated‐β‐galactosidase activity, p16INK 4a and plasminogen activator inhibitor‐1 expression, and elevated telomerase activity. Kallistatin blocked H2O2‐induced superoxide formation, NADPH oxidase levels and VCAM‐1, ICAM‐1, IL‐6 and miR‐34a synthesis. Kallistatin reversed H2O2‐mediated inhibition of endothelial nitric oxide synthase (eNOS), SIRT1, catalase and superoxide dismutase (SOD)‐2 expression, and kallistatin alone stimulated the synthesis of these antioxidant enzymes. Moreover, kallistatin's anti‐senescence and anti‐oxidant effects were attributed to SIRT1‐mediated eNOS pathway. Kallistatin, via interaction with tyrosine kinase, up‐regulated Let‐7g, whereas Let‐7g inhibitor abolished kallistatin's effects on miR‐34a and SIRT1/eNOS synthesis, leading to inhibition of senescence, oxidative stress and inflammation. Furthermore, lung endothelial cells isolated from endothelium‐specific kallistatin knockout mice displayed marked reduction in mouse kallistatin levels. Kallistatin deficiency in mouse endothelial cells exacerbated senescence, oxidative stress and inflammation compared to wild‐type mouse endothelial cells, and H2O2 treatment further magnified these effects. Kallistatin deficiency caused marked reduction in Let‐7g, SIRT1, eNOS, catalase and SOD‐1 mRNA levels, and elevated miR‐34a synthesis in mouse endothelial cells. These findings indicate that endogenous kallistatin through novel mechanisms protects against endothelial senescence by modulating Let‐7g‐mediated miR‐34a‐SIRT1‐eNOS pathway.

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Senescence-Induced Oxidative Stress Causes Endothelial Dysfunction

Cited by 99 publications

References 57 publications

The role of senescence, telomere dysfunction and shelterin in vascular aging

The role of senescence, telomere dysfunction and shelterin in vascular aging

Piwi-interacting RNAs play a role in vitamin C-mediated effects on endothelial aging

Kallistatin attenuates endothelial senescence by modulating Let‐7g‐mediated miR‐34a‐SIRT1‐eNOS pathway

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