Apoptosis Signal-Regulating Kinase 1 Mediates Cellular Senescence Induced by High Glucose in Endothelial Cells

Yokoi, Taishi; Fukuo, Keisuke; Yasuda, Osamu; Hotta, Mizuo; Miyazaki, Jun‐ichi; Takemura, Yukihiro; Kawamoto, Hidenobu; Ichijo, Hidenori; Ogihara, Toshio

doi:10.2337/db05-1607

Cited by 153 publications

(116 citation statements)

References 43 publications

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“…27 We considered STZ-diabetic mice suitable for investigation of clinical settings. STZ-treated mice with and without pitavastatin administration had elevated plasma glucose associated with decreased plasma insulin level compared with control mice (Supplemental Figure IVA).…”

Section: Administration Of Pitavastatin Inhibits Vascular Endothelialmentioning

confidence: 99%

Induction of Endothelial Nitric Oxide Synthase, SIRT1, and Catalase by Statins Inhibits Endothelial Senescence Through the Akt Pathway

Ota

Eto

Kano

et al. 2010

ATVB

188

130

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Objective-Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have pleiotropic vascular protective effects besides cholesterol lowering. Recently, experimental and clinical studies have indicated that senescence of endothelial cells is involved in endothelial dysfunction and atherogenesis. Therefore, the present study was performed to determine whether statins would reduce endothelial senescence and to clarify the molecular mechanisms underlying the antisenescent property of statins. Methods and Results-Senescent human umbilical vein endothelial cells were induced by hydrogen peroxide (H 2 O 2 ), as judged by senescence-associated ␤-galactosidase assay and cell morphological appearance. Atorvastatin, pravastatin, and pitavastatin inhibited the oxidative stress induced-endothelial senescence. These statins phosphorylated Akt at Ser473 and subsequently led to increased expression of endothelial nitric oxide synthase (eNOS), SIRT1, and catalase. Treatment with LY294002 or Akt short interfering RNA decreased the eNOS activation, SIRT1 expression, and antisenescent property of atorvastatin. Moreover, in streptozotocin-diabetic mice, administration of pitavastatin increased eNOS, SIRT1, and catalase expression and decreased endothelial senescence, but levels remained unaltered in Sirt1 knockout mice. Key Words: endothelium Ⅲ nitric oxide synthase Ⅲ SIRT1 Ⅲ senescence Ⅲ statin T he 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, are effective in lowering the plasma concentration of low-density lipoprotein cholesterol and are widely used in patients with hypercholesterolemia. Recently, experimental and clinical evidence has indicated that the pleiotropic effects of statins involve improvement or restoration of endothelial function, enhanced activity of endothelial nitric oxide synthase (eNOS), and decreased oxidative stress. 1 Oxidative stress is implicated in the pathogenesis of cardiovascular diseases, such as atherosclerosis. 2 Excessive production of reactive oxygen species inflicts damage on endothelial cells and leads to the onset of endothelial senescence. Senescence of endothelial cells is involved in endothelial dysfunction and atherogenesis. 3 Histological study of human atherosclerotic lesions has demonstrated the existence of endothelial cells that exhibit the morphological features of senescence. 4 Assmus et al have shown that statins reduce senescence and increase proliferation of endothelial progenitor cells. 5 In Saccharomyces cerevisiae, the silent information regulator 2 (Sir2) family of genes governs budding exhaustion and replicative life span. 6,7 Sir2 has been identified as an NAD ϩ -dependent histone deacetylase and is responsible for maintenance of chromatin silencing and genome stability. 8 Sir2 genes are conserved during evolution, and 7 homologs of sirtuins (Sirt1 to Sirt7) have been cloned in mammals. Mammalian sirtuin 1 (Sirt1), the closest homolog of Sir2, regulates the cell cycle, senescence, apoptosis, and metabolism by interacting with a number of mo...

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Section: Administration Of Pitavastatin Inhibits Vascular Endothelialmentioning

confidence: 99%

Induction of Endothelial Nitric Oxide Synthase, SIRT1, and Catalase by Statins Inhibits Endothelial Senescence Through the Akt Pathway

Ota

Eto

Kano

et al. 2010

ATVB

188

130

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“…Third, high FPG levels have been shown to induce activation of signaling involved in endothelial apoptosis. 21 Fourth, hyperglycemic individuals are hyperinsulinemic, and the high insulin levels may promote increased ventricular mass and decreased cardiac output. 22 Fifth, hyperglycemic individuals also are insulin resistant, which is an independent predictor of incident CHF after accounting for diabetes or obesity.…”

Section: Potential Mechanismsmentioning

confidence: 99%

Glucose Levels Predict Hospitalization for Congestive Heart Failure in Patients at High Cardiovascular Risk

et al. 2007

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Background-Patients with diabetes mellitus (DM) are at high risk of developing congestive heart failure (CHF).However, the relationships between glucose levels and CHF in people with or without a history of DM have not been well characterized. . Interim analyses blinded for randomized treatment were performed to compare baseline fasting plasma glucose with the adjusted CHF event rate at a mean follow-up of 886 days. Multivariable Cox regression models were performed, and associations were reported as hazard ratios and 95% confidence intervals. Among all subjects (mean age, 67 years; 69% men), of whom 11 708 (37%) had known DM and 1006 (3.2%) had newly diagnosed DM at baseline, 668 patients were hospitalized for CHF during follow-up. After adjustment for age and sex, a 1-mmol/L-higher fasting plasma glucose was associated with a 1.10-fold-increased risk of CHF hospitalization (95% confidence interval, 1.08 to 1.12; PϽ0.0001). The association persisted after adjustment for age, sex, smoking, previous myocardial infarction, hypertension, waist-to-hip ratio, creatinine, DM, and use of aspirin, ␤-blockers, or statins (hazard ratio, 1.05; 95% confidence interval, 1.02 to 1.08; PϽ0.001). Conclusions-Fasting plasma glucose is an independent predictor of hospitalization for CHF in high-risk subjects. These data provide theoretical support for potential direct beneficial effects of glucose lowering in reducing the risk of CHF and suggests the need for specific studies targeted at this issue.

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“…The role of the well known tumour suppressor transcription factor p53 in diabetes has long been undervalued. Research has recently focused on p53 activation in human endothelial cells exposed to high glucose levels [14], showing how p53-induced cellular senescence in vascular cells might contribute to accelerated ageing and atherosclerosis [15,16]. Furthermore, studies showed that inhibition of p53 activity in mouse adipose tissue markedly decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease.…”

Section: Introductionmentioning

confidence: 99%

Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells

et al. 2011

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Aims/hypothesis Damage persists in HUVECs exposed to a constant high glucose concentration long after glucose normalisation, a phenomenon termed 'metabolic memory'. Evaluation of the effects of exposure of HUVECs to oscillating high glucose on the induction of markers of oxidative stress and DNA damage (phospho-γ-histone H2AX and PKCδ) and onset of metabolic memory, and the possible role of the tumour suppressor transcriptional factor p53 is of pivotal interest. Methods HUVECs were incubated for 3 weeks in 5 or 25 mmol/l glucose or oscillating glucose (24 h in 5 mmol/l glucose followed by 24 h in 25 mmol/l glucose) or for 1 week in constant 5 mmol/l glucose after being exposed for 2 weeks to continuous 25 mmol/l high glucose or oscillating glucose. Transcriptional activity of p53 was also evaluated in the first 24 h after high glucose exposure. Results High constant glucose upregulated phospho-γ-histone H2AX and protein kinase C (PKC)δ compared with control. Oscillating glucose was even more effective than both normal and constant high glucose. Both constant and oscillating glucose resulted in a memory effect, which was more pronounced in the oscillating condition. Transcriptional activity of p53 peaked 6 h after glucose exposure, showing a predicted oscillatory behaviour. Conclusions/interpretation Exposure to oscillating glucose was more deleterious than constant high glucose and induced a metabolic memory after glucose normalisation. Hyperactivation of p53 during glucose oscillation might be due to the absence of consistent feedback inhibition during each glucose spike and might account for the worse outcome of this condition.

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Apoptosis Signal-Regulating Kinase 1 Mediates Cellular Senescence Induced by High Glucose in Endothelial Cells

Cited by 153 publications

References 43 publications

Induction of Endothelial Nitric Oxide Synthase, SIRT1, and Catalase by Statins Inhibits Endothelial Senescence Through the Akt Pathway

Induction of Endothelial Nitric Oxide Synthase, SIRT1, and Catalase by Statins Inhibits Endothelial Senescence Through the Akt Pathway

Glucose Levels Predict Hospitalization for Congestive Heart Failure in Patients at High Cardiovascular Risk

Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells

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