scholarly journals Oxidative Stress Induces Endothelial Cell Senescence via Downregulation of Sirt6

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Rong Liu ◽  
Hua Liu ◽  
Yonju Ha ◽  
Ronald G. Tilton ◽  
Wenbo Zhang
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
Endothelial Cell ◽  
Vascular Complications ◽  
Cell Senescence ◽  
Diabetic Vascular Complications ◽  
Key Factor ◽  
And Oxidative Stress ◽  
Vascular Cell Senescence

Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associatedβ-galactosidase activity. Additionally, H2O2treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated) retinoblastoma (Rb) protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.

scholarly journals Application of Oxidative Stress to a Tissue-Engineered Vascular Aging Model Induces Endothelial Cell Senescence and Activation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1292
Author(s):  
Ellen E. Salmon ◽  
Jason J. Breithaupt ◽  
George A. Truskey
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Adhesion Molecule ◽  
Dermal Fibroblasts ◽  
Cell Senescence ◽  
Mural Cell ◽  
Aged Patients ◽  
H2o2 Treatment ◽  
Vascular Cell

Clinical studies have established a connection between oxidative stress, aging, and atherogenesis. These factors contribute to senescence and inflammation in the endothelium and significant reductions in endothelium-dependent vasoreactivity in aged patients. Tissue-engineered blood vessels (TEBVs) recapitulate the structure and function of arteries and arterioles in vitro. We developed a TEBV model for vascular senescence and examined the relative influence of endothelial cell and smooth muscle cell senescence on vasoreactivity. Senescence was induced in 2D endothelial cell cultures and TEBVs by exposure to 100 µM H2O2 for one week to model chronic oxidative stress. H2O2 treatment significantly increased senescence in endothelial cells and mural cells, human neonatal dermal fibroblasts (hNDFs), as measured by increased p21 levels and reduced NOS3 expression. Although H2O2 treatment induced senescence in both the endothelial cells (ECs) and hNDFs, the functional effects on the vasculature were endothelium specific. Expression of the leukocyte adhesion molecule vascular cell adhesion molecule 1 (VCAM-1) was increased in the ECs, and endothelium-dependent vasodilation decreased. Vasoconstriction and endothelium-independent vasodilation were preserved despite mural cell senescence. The results suggest that the functional effects of vascular cell senescence are dominated by the endothelium.

Involvement of microparticles in diabetic vascular complications

2011 ◽  
Vol 106 (08) ◽  
pp. 310-321 ◽  
Author(s):  
Gala Tsimerman ◽  
Ariel Roguin ◽  
Anat Bachar ◽  
Eyal Melamed ◽  
Benjamin Brenner ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
Endothelial Cell ◽  
Coronary Artery ◽  
Vascular Complications ◽  
Tube Formation ◽  
Foot Ulcers ◽  
Healthy Controls ◽  
Artery Disease

SummaryType 2 diabetes mellitus (T2DM) is associated with increased coagulability and vascular complications. Circulating microparticles (MPs) are involved in thrombosis, inflammation, and angiogenesis. However, the role of MPs in T2DM vascular complications is unclear. We characterised the cell origin and pro-coagulant profiles of MPs obtained from 41 healthy controls and 123 T2DM patients with coronary artery disease, retinopathy and foot ulcers. The effects of MPs on endothelial cell coagulability and tube formation were evaluated. Patients with severe diabetic foot ulcers expressed the highest levels of MPs originated from platelet and endothelial cells and negatively-charged phospholipidbearing MPs. MP coagulability, calculated from MP tissue factor (TF) and TF pathway inhibitor (TFPI) ratio, was low in healthy controls and in diabetic retinopathy patients (<0.7) but high in patients with coronary artery disease and foot ulcers (>1.8, p≥0.002). MPs of all T2DM patients induced a more than two-fold increase in endothelial cell TF (antigen and gene expression) but did not affect TFPI levels. Tube networks were longest and most stable in endothelial cells that were incubated with MPs of healthy controls, whereas no tube formation occurred in MPs of diabetic patients with coronary artery disease. MPs of diabetic retinopathy and diabetic foot ulcer patients induced branched tube networks that were unstable and collapsed over time. This study demonstrates that MP characteristics are related to the specific type of vascular complications and may serve as a bio-marker for the procoagulant state and vascular pathology in patients with T2DM.

scholarly journals Pharmacological Effects of Methotrexate and Infliximab in a Rats Model of Diet-Induced Dyslipidemia and Beta-3 Overexpression on Endothelial Cells

2021 ◽  
Vol 10 (14) ◽  
pp. 3143
Author(s):  
Denisa-Mădălina Zălar ◽  
Cristina Pop ◽  
Elena Buzdugan ◽  
Bela Kiss ◽  
Maria-Georgia Ştefan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Drug Treatment ◽  
Serum Lipid ◽  
Vascular Complications ◽  
Lipid Profiles ◽  
Histopathological Analysis ◽  
Standard Diet ◽  
Sprague Dawley ◽  
And Oxidative Stress

Background: Hyperlipidemia and inflammation are critical components in the pathophysiology of endothelial disorder, which can lead to vascular complications. Our study aimed to evaluate the effects of immunomodulatory therapy (methotrexate and infliximab) in a diet-induced hyperlipidemia rat model. Methods: Sprague-Dawley (wild type (WT), male, n = 32) rats were divided into four groups: one group fed with standard diet (SD), one group fed with high lipid diet (HLD), and two groups that received HLD and drug treatment (methotrexate (Mtx) or infliximab (Ifx)). In order to evaluate if modifications to the endothelial cells may influence the risk of vascular complications following hyperlipidemia or treatment reactivity, each group was doubled by a rats group that overexpressed beta-3 receptors on the endothelial cells (transgenic (TG-beta 3), male, n = 32). Serum lipid profile, liver enzymes, oxidative stress, and inflammation markers were determined. Histopathologic analysis of the liver and aorta was performed. Results: After 9 weeks of HLD, rats exhibited significant pathologic serum lipid profiles, elevated oxidative stress, and pro-inflammatory markers. Additionally, the aortic histopathological analysis revealed aorta media-intima thickening (p < 0.05) in the transgenic group. Methotrexate and infliximab significantly decreased inflammation and oxidative stress parameters, but presented opposing effects on lipid profiles (methotrexate decreased, whereas infliximab increased the atherosclerosis index). Drug treatment decreased the aorta media-intima thickness (p < 0.05) only in transgenic rats. Conclusions: HLD was associated with hyperlipidemia, inflammation and oxidative stress. The overexpression of beta-3 receptors on endothelial cells increased aortic thickening in response to the HLD. Methotrexate and infliximab reduced oxidative stress and inflammation in all groups, but led to favorable histopathologic vascular results only in the transgenic groups.

scholarly journals Angelica sinensis has inherent endothelial cell toxicity at high concentrations but can also protect the vascular endothelium from oxidative stress-induced injury at moderate concentrations

2011 ◽  
Vol 1 (1) ◽  
pp. 8
Author(s):  
Miko Yamada ◽  
Betty Pat ◽  
Glenda Gobe ◽  
Ken Wojcikowski
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Heme Oxygenase ◽  
Angelica Sinensis ◽  
Molecular Characteristics ◽  
Heme Oxygenase 1 ◽  
High Concentrations ◽  
Induced Apoptosis ◽  
And Oxidative Stress

Hypoxia and oxidative stress are important factors in the pathogenesis of many acute forms of injury, especially acute kidney injury. Apoptosis is a key mode of endothelial cell death from oxidative stress. Minimising the detrimental effects of oxidative stress is necessary to reduce injury, and new treatment strategies are constantly being sought. The aim of this study was to investigate the ability of an aqueous/methanol extract of Angelica sinensis (AS) root (Chinese names Danggui, Dong quai, Donggui) to protect endothelium from hypoxia and oxidative stress. This was compared in specialised kidney endothelium (renal medullary vascular endothelial cells; RMVEC) versus central endothelium (aortic endothelial cells; AEC). Toxicity of various strengths of AS was first tested in RMVEC and AEC using % apoptosis and mitosis as outcomes. Morphological and molecular characteristics of apoptosis and mitosis, and the effect of AS on heme-oxygenase-1, a marker of cellular response to oxidative stress, were also investigated. The results showed that, at concentrations of 2500µg/mL or greater, AS significantly increased apoptosis in RMVEC and AEC (P&lt;0.05), however concentrations of 2000 µg/mL or less were non-toxic and also non-mitogenic. Endothelial cells were then treated with hydrogen peroxide (0.8 mM for RMVEC; 0.6 mM for AEC) for oxidative stress, with and without 2000 µg/mL AS. AS significantly inhibited oxidant-induced apoptosis (P&lt;0.05) but had little effect on mitosis. AS also increased heme-oxygenase-1, but only in AEC. AS extracts may have some inherent toxicity at high concentrations, but with careful analysis of non-toxic levels, both renal and central endothelium benefited from AS against oxidative stress-induced apoptosis, without inducing excessive mitosis, and AS may find application in some oxidant-induced disease.

scholarly journals Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression

2021 ◽  
Vol 8 ◽  
Author(s):  
Haicheng Li ◽  
Ting Li ◽  
Heting Wang ◽  
Xuemin He ◽  
Ying Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
Endothelial Cell ◽  
Tight Junction ◽  
Cell Injury ◽  
Cell Physiology ◽  
Sequencing Analysis ◽  
Vascular Endothelial ◽  
Endothelial Cell Injury

Purpose: Diabetic retinopathy (DR) is one of the most common diabetic microvascular complications. However, the pathogenesis of DR has not yet been fully elucidated. This study aimed to discover novel and key molecules involved in the pathogenesis of DR, which could potentially be targets for therapeutic DR intervention.Methods: To identify potential genes involved in the pathogenesis of DR, we analyzed the public database of neovascular membranes (NVMs) from patients with proliferative diabetic retinopathy (PDR) and healthy controls (HCs) (GSE102485, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102485). Further, we compared these findings by performing RNA-sequencing analysis of peripheral blood mononuclear cells (PBMC) from patients with DR, control patients with non-complicated diabetes mellitus (DMC), and HCs. To determine the critical role of candidate genes in DR, knockdown or knockout was performed in human retinal vascular endothelial cells (HRVECs). The oxidative stress pathway, as well as tight junction integrity, was analyzed.Results: Transcriptional profiles showed distinct patterns between the NVMs of patients with DR and those of the HCs. Those genes enriched in either extracellular matrix (ECM)-receptor interaction or focal adhesion pathways were considerably upregulated. Both pathways were important for maintaining the integrity of retinal vascular structure and function. Importantly, the gene encoding the matricellular protein CCN1, a key gene in cell physiology, was differentially expressed in both pathways. Knockdown of CCN1 by small interfering RNA (siRNA) or knockout of CCN1 by the CRISPR-Cas9 technique in HRVECs significantly increased the levels of VE-cadherin, reduced the level of NADPH oxidase 4 (NOX4), and inhibited the generation of reactive oxygen species (ROS).Conclusion: The present study identifies CCN1 as an important regulator in the pathogenesis of DR. Increased expression of CCN1 stimulates oxidative stress and disrupts tight junction integrity in endothelial cells by inducing NOX4. Thus, targeting the CCN1/NOX4 axis provides a therapeutic strategy for treating DR by alleviating endothelial cell injury.

scholarly journals High stretch induces endothelial dysfunction accompanied by oxidative stress and actin remodeling in human saphenous vein endothelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
T. Girão-Silva ◽  
M. H. Fonseca-Alaniz ◽  
J. C. Ribeiro-Silva ◽  
J. Lee ◽  
N. P. Patil ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Saphenous Vein ◽  
Saphenous Vein Graft ◽  
Artery Bypass ◽  
Bypass Graft ◽  
Human Saphenous Vein ◽  
Actin Remodeling

AbstractThe rate of the remodeling of the arterialized saphenous vein conduit limits the outcomes of coronary artery bypass graft surgery (CABG), which may be influenced by endothelial dysfunction. We tested the hypothesis that high stretch (HS) induces human saphenous vein endothelial cell (hSVEC) dysfunction and examined candidate underlying mechanisms. Our results showed that in vitro HS reduces NO bioavailability, increases inflammatory adhesion molecule expression (E-selectin and VCAM1) and THP-1 cell adhesion. HS decreases F-actin in hSVECs, but not in human arterial endothelial cells, and is accompanied by G-actin and cofilin’s nuclear shuttling and increased reactive oxidative species (ROS). Pre-treatment with the broad-acting antioxidant N-acetylcysteine (NAC) supported this observation and diminished stretch-induced actin remodeling and inflammatory adhesive molecule expression. Altogether, we provide evidence that increased oxidative stress and actin cytoskeleton remodeling play a role in HS-induced saphenous vein endothelial cell dysfunction, which may contribute to predisposing saphenous vein graft to failure.

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