Endothelial cells maintain a reduced redox environment even as mitochondrial function declines

2002 ◽  
Vol 283 (6) ◽  
pp. C1675-C1686 ◽  
Author(s):  
Ricarda Carlisle ◽  
Carol Ann Rhoads ◽  
Tak Yee Aw ◽  
Lynn Harrison
Keyword(s):  
Endothelial Cells ◽  
Oxygen Consumption ◽  
Genomic Instability ◽  
Mitochondrial Function ◽  
Replicative Senescence ◽  
Umbilical Vein ◽  
Nuclear Genome ◽  
Mitochondrial Mass ◽  
Atp Production ◽  
Age Related

Human umbilical vein endothelial cells (HUVECs) are an endothelial model of replicative senescence. Oxidative stress, possibly due to dysfunctional mitochondria, is believed to play a key role in replicative senescence and atherosclerosis, an age-related vascular disease. In this study, we determined the effect of cell division on genomic instability, mitochondrial function, and redox status in HUVECs that were able to replicate for ∼60 cumulative population doublings (CPD). After 20 CPD, the nuclear genome deteriorated and the protein content of the cell population increased. This indicated an increase in cell size, which was accompanied by an increase in oxygen consumption, ATP production, and mitochondrial genome copy number and ∼10% increase in mitochondrial mass. The antioxidant capacity increased, as seen by an increase in reduced glutathione, glutathione peroxidase, GSSG reductase, and glucose-6-phosphate dehydrogenase. However, by CPD 52, the latter two enzymes decreased, as well as the ratio of mitochondrial-to-nuclear genome copies, the mitochondrial mass, and the oxygen consumption per milligram of protein. Our results signify that HUVECs maintain a highly reducing (GSH) environment as they replicate despite genomic instability and loss of mitochondrial function.

scholarly journals Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 356 ◽  
Author(s):  
Alessia Lo Curto ◽  
Simona Taverna ◽  
Maria Assunta Costa ◽  
Rosa Passantino ◽  
Giuseppa Augello ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Fabry Disease ◽  
Healthy Subjects ◽  
Aging Process ◽  
Replicative Senescence ◽  
Ex Vivo ◽  
Umbilical Vein ◽  
Quantitative Polymerase Chain Reaction ◽  
Premature Aging

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by lysosomal accumulation of glycosphingolipids in a wide variety of cytotypes, including endothelial cells (ECs). FD patients experience a significantly reduced life expectancy compared to the general population; therefore, the association with a premature aging process would be plausible. To assess this hypothesis, miR-126-3p, a senescence-associated microRNA (SA-miRNAs), was considered as an aging biomarker. The levels of miR-126-3p contained in small extracellular vesicles (sEVs), with about 130 nm of diameter, were measured in FD patients and healthy subjects divided into age classes, in vitro, in human umbilical vein endothelial cells (HUVECs) “young” and undergoing replicative senescence, through a quantitative polymerase chain reaction (qPCR) approach. We confirmed that, in vivo, circulating miR-126 levels physiologically increase with age. In vitro, miR-126 augments in HUVECs underwent replicative senescence. We observed that FD patients are characterized by higher miR-126-3p levels in sEVs, compared to age-matched healthy subjects. We also explored, in vitro, the effect on ECs of glycosphingolipids that are typically accumulated in FD patients. We observed that FD storage substances induced in HUVECs premature senescence and increased of miR-126-3p levels. This study reinforces the hypothesis that FD may aggravate the normal aging process.

scholarly journals Impaired Mitochondrial Fusion and Oxidative Phosphorylation Triggered by High Glucose Is Mediated by Tom22 in Endothelial Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-23 ◽  
Author(s):  
Yi Zeng ◽  
Qi Pan ◽  
Xiaoxia Wang ◽  
Dongxiao Li ◽  
Yajun Lin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Mitochondrial Dynamics ◽  
Umbilical Vein ◽  
Vascular Complications ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Atp Production

Much evidence demonstrates that mitochondrial dysfunction plays a crucial role in the pathogenesis of vascular complications of diabetes. However, the signaling pathways through which hyperglycemia leads to mitochondrial dysfunction of endothelial cells are not fully understood. Here, we treated human umbilical vein endothelial cells (HUVECs) with high glucose and examined the role of translocase of mitochondrial outer membrane (Tom) 22 on mitochondrial dynamics and cellular function. Impaired Tom22 expression and protein expression of oxidative phosphorylation (OXPHOS) as well as decreased mitochondrial fusion were observed in HUVECs treated with high glucose. The deletion of Tom22 resulted in reduced mitochondrial fusion and ATP production and increased apoptosis in HUVECs. The overexpression of Tom22 restored the balance of mitochondrial dynamics and OXPHOS disrupted by high glucose. Importantly, we found that Tom22 modulates mitochondrial dynamics and OXPHOS by interacting with mitofusin (Mfn) 1. Taken together, our findings demonstrate for the first time that Tom22 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following high-glucose exposure.

scholarly journals Effects of GH/IGF on the Aging Mitochondria

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1384 ◽  
Author(s):  
Sher Bahadur Poudel ◽  
Manisha Dixit ◽  
Maria Neginskaya ◽  
Karthik Nagaraj ◽  
Evgeny Pavlov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Hormone ◽  
Cell Differentiation ◽  
Growth Factor ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Cellular Aging ◽  
Mitochondrial Mass ◽  
Atp Production ◽  
And Function

The mitochondria are key organelles regulating vital processes in the eukaryote cell. A decline in mitochondrial function is one of the hallmarks of aging. Growth hormone (GH) and the insulin-like growth factor-1 (IGF-1) are somatotropic hormones that regulate cellular homeostasis and play significant roles in cell differentiation, function, and survival. In mammals, these hormones peak during puberty and decline gradually during adulthood and aging. Here, we review the evidence that GH and IGF-1 regulate mitochondrial mass and function and contribute to specific processes of cellular aging. Specifically, we discuss the contribution of GH and IGF-1 to mitochondrial biogenesis, respiration and ATP production, oxidative stress, senescence, and apoptosis. Particular emphasis was placed on how these pathways intersect during aging.

scholarly journals Salidroside Stimulates Mitochondrial Biogenesis and Protects against H2O2-Induced Endothelial Dysfunction

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Shasha Xing ◽  
Xiaoyan Yang ◽  
Wenjing Li ◽  
Fang Bian ◽  
Dan Wu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Transcription Factor ◽  
Endothelial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Umbilical Vein ◽  
Adenosine Monophosphate ◽  
No Production ◽  
Peroxisome Proliferator ◽  
Atp Production

Salidroside (SAL) is an active component ofRhodiola roseawith documented antioxidative properties. The purpose of this study is to explore the mechanism of the protective effect of SAL on hydrogen peroxide- (H2O2-) induced endothelial dysfunction. Pretreatment of the human umbilical vein endothelial cells (HUVECs) with SAL significantly reduced the cytotoxicity brought by H2O2. Functional studies on the rat aortas found that SAL rescued the endothelium-dependent relaxation and reduced superoxide anion (O2∙-) production induced by H2O2. Meanwhile, SAL pretreatment inhibited H2O2-induced nitric oxide (NO) production. The underlying mechanisms involve the inhibition of H2O2-induced activation of endothelial nitric oxide synthase (eNOS), adenosine monophosphate-activated protein kinase (AMPK), and Akt, as well as the redox sensitive transcription factor, NF-kappa B (NF-κB). SAL also increased mitochondrial mass and upregulated the mitochondrial biogenesis factors, peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1α), and mitochondrial transcription factor A (TFAM) in the endothelial cells. H2O2-induced mitochondrial dysfunction, as demonstrated by reduced mitochondrial membrane potential (Δψm) and ATP production, was rescued by SAL pretreatment. Taken together, these findings implicate that SAL could protect endothelium against H2O2-induced injury via promoting mitochondrial biogenesis and function, thus preventing the overactivation of oxidative stress-related downstream signaling pathways.

scholarly journals H2O2 downregulate SIRT7`s protective role of endothelial premature dysfunction via microRNA-335-5p

2022 ◽  
Author(s):  
Yixin Liu ◽  
Jinyu Yang ◽  
Xi Yang ◽  
Peng Lai ◽  
Yi Mou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Endothelial Cells ◽  
Umbilical Vein ◽  
Protective Role ◽  
Atherosclerotic Cardiovascular Disease ◽  
Contributing Factors ◽  
Age Related ◽  
Underlying Mechanisms ◽  
Umbilical Vein Endothelial Cells

Endothelial senescence is believed to constitute the initial pathogenesis of the atherosclerotic cardiovascular disease (ASCVD). MicroRNA-335-5p (miR-335-5p) expression is significantly upregulated in oxidative stress-induced endothelial cells (ECs). Sirtuin7 (SIRT7) is considered to prevent EC senescence, yet data on its response to ASCVD risk factors are limited. This study analyzed the elevated levels of miR-335-5p and the decreased levels of SIRT7 in human umbilical vein endothelial cells (HUVECs) , and found that high glucose, tumour necrosis factor-α (TNF-α), and H2O2 are the three contributing factors that induced cellular senescence. The current study also assessed premature endothelial senescence and decreased proliferation, adhesion, migration, and nitric oxide secretion in HUVECs with these risk factors together with SIRT7-siRNA transfection. It found that the miR-335-5p inhibitor attenuated the downregulation of SIRT7 expression induced by oxidative stress in HUVECs, and SIRT7 overexpression exerts a rescue effect against miR-335-5p induced endothelial dysfunction. Furthermore, the direct binding of miR-335-5p to SIRT7 was observed in HEK-293T. Therefore, it can be inferred that miR-335-5p downregulates the expression of SIRT7 in human cells. Current findings may provide deeper insights into the underlying mechanisms of endothelial senescence and potential therapeutic targets of ASCVD as well as other age-related diseases.

Abstract P122: Mitochondrial Transcription Factor 2B Regulates Endothelial Cell Morphology

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Steven J Forrester ◽  
Tatsuo Kawai ◽  
Katherine J Elliot ◽  
Kunie Eguchi ◽  
Joon Y Park ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Cardiovascular Diseases ◽  
Cell Morphology ◽  
Mitochondrial Function ◽  
Umbilical Vein ◽  
Fold Increase ◽  
Mitochondrial Transcription ◽  
Signaling Mechanism ◽  
Mitochondrial Transcription Factor

Mitochondrial dysfunction, such as observed in endothelial cells, has been implicated in various cardiovascular diseases including, hypertension and atherosclerosis. Mitochondrial transcription factor 2B (TFB2M) is an essential component to maintain proper transcriptional and functional control of mitochondrial DNA. As well, elongation of endothelial cells is a characteristic of atheroprotective regions within the vasculature, and the relationship between the mitochondria and EC shape is currently unknown. The aim of our study is to investigate the hypothesis that TFB2M has a novel role in enhancing endothelial function. Human umbilical vein endothelial cells (HUVECs) were harvested 72 hours after adenoviral transduction with TFB2M (100 moi). HUVECs transduced with TFB2M showed an elongated cell morphology when compared to GFP control. To further investigate the effect of TFB2M on regulating mitochondrial function and cell shape, immunoblotting was carried out for markers involved in mitochondrial function/dynamics and markers indicative of cytoskeleton reorganization. TFB2M transduction resulted in increased expression of mitochondrial biogenesis marker VDAC (2.6 fold increase), mitochondrial fusion protein MFN2 (2.1 fold increase), and phosphorylated myosin phosphatase targeting protein MYPT1 at Thr850 (2.2 fold increase, p < 0.05 for all proteins). Additionally, fluorescence microscopy showed enhanced mitochondrial fluorescence in TFB2M transduced cells using mitotracker red staining (3.5 fold increase, p < 0.001). These data indicate that TFB2M has a previously undiscovered function contributing to altered EC function and shape, potentially through a novel mitochondrial retrograde signaling mechanism. Further research will focus on distinguishing the exact mechanisms culminating in a protective EC phenotype and the beneficial role of endothelial TFB2M-mediated enhanced mitochondrial function in the treatment of EC dysfunction associated with various cardiovascular diseases.

scholarly journals Coenzyme Q10 Prevents Senescence and Dysfunction Caused by Oxidative Stress in Vascular Endothelial Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Jia Huo ◽  
Zhe Xu ◽  
Kazunori Hosoe ◽  
Hiroshi Kubo ◽  
Hiroki Miyahara ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Oxidative Damage ◽  
Mitochondrial Function ◽  
Coenzyme Q10 ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Reduced Form ◽  
No Production

Oxidative damage in endothelial cells is proposed to play an important role in endothelial dysfunction and atherogenesis. We previously reported that the reduced form of coenzyme Q10 (CoQ10H2) effectively inhibits oxidative stress and decelerates senescence in senescence-accelerated mice. Here, we treated human umbilical vein endothelial cells (HUVECs) with H2O2 and investigated the protective effect of CoQ10H2 against senescence, oxidative damage, and reduction in cellular functions. We found that CoQ10H2 markedly reduced the number of senescence-associated β-galactosidase-positive cells and suppressed the expression of senescence-associated secretory phenotype-associated genes in H2O2-treated HUVECs. Furthermore, CoQ10H2 suppressed the generation of intracellular reactive oxygen species (ROS) but promoted NO production that was accompanied by increased eNOS expression. CoQ10H2 prevented apoptosis and reductions in mitochondrial function and reduced migration and tube formation activity of H2O2-treated cells. The present study indicated that CoQ10H2 protects endothelial cells against senescence by promoting mitochondrial function and thus could delay vascular aging.

Oxygen dependence of respiration in coupled and uncoupled endothelial cells

1996 ◽  
Vol 271 (6) ◽  
pp. C2053-C2061 ◽  
Author(s):  
R. Steinlechner-Maran ◽  
T. Eberl ◽  
M. Kunc ◽  
R. Margreiter ◽  
E. Gnaiger
Keyword(s):  
Endothelial Cells ◽  
Oxygen Consumption ◽  
Respiratory Rate ◽  
Oxygen Diffusion ◽  
Umbilical Vein ◽  
Carbonyl Cyanide ◽  
Coupled Cells ◽  
Rate Of Oxygen Consumption ◽  
Cell Densities ◽  
Umbilical Vein Endothelial Cells

We studied the oxygen dependence of respiration in cultured human umbilical vein endothelial cells by use of high-resolution respirometry. The rate of oxygen consumption varied from 30 to 50 pmol O2.s-1.(10(6) cells)-1 over a sixfold range of cell densities. Respiration was stimulated up to 3.5-fold by uncoupling with carbonyl cyanide p-trifluoromethoxyphenylhydrazone or 2,4-dinitrophenol, and the PO2 at half-maximal respiration (P50) increased from 0.05 to 0.12 kPa (0.3 to 0.9 Torr) with respiratory rate. P50 decreased to a minimum of 0.02 kPa when uncoupled cells were inhibited to control levels. Differences in cell size explained a variation of approximately 0.015 kPa in P50 at similar respiratory rates per cell. Oxygen diffusion to mitochondria contributed maximally 30% to the regulation of P50 in coupled cells, as deduced from the shallow slope of the flux dependence of P50 in uncoupled-inhibited cells compared with the slope in coupled cells. Therefore 70% of the flux dependence of P50 in coupled cells was caused by changes in metabolic state, which correlated with respiratory rate.

scholarly journals Polydatin Prevents Methylglyoxal-Induced Apoptosis through Reducing Oxidative Stress and Improving Mitochondrial Function in Human Umbilical Vein Endothelial Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ningbo Pang ◽  
Tangting Chen ◽  
Xin Deng ◽  
Ni Chen ◽  
Rong Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Mitochondrial Function ◽  
Cell Apoptosis ◽  
Umbilical Vein ◽  
Ros Generation ◽  
Mitochondrial Morphology ◽  
Human Umbilical Vein ◽  
Induced Apoptosis ◽  
Umbilical Vein Endothelial Cells

Methylglyoxal (MGO), an active metabolite of glucose, has been reported to induce vascular cell apoptosis in diabetic complication. Polydatin (PD), a small natural compound from Polygonum cuspidatum, has a number of biological functions, such as antioxidative, anti-inflammatory, and nephroprotective properties. However, the protective effects of PD on MGO-induced apoptosis in endothelial cells remain to be elucidated. In this study, human umbilical vein endothelial cells (HUVECs) were used to explore the effects of PD on MGO-induced cell apoptosis and the possible mechanism involved. HUVECs were pretreated with PD for 2 h, followed by stimulation with MGO. Then cell apoptosis, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) impairment, mitochondrial morphology alterations, and Akt phosphorylation were assessed. The results demonstrated that PD significantly prevented MGO-induced HUVEC apoptosis. PD pretreatment also significantly inhibited MGO-induced ROS production, MMP impairment, mitochondrial morphology changes, and Akt dephosphorylation. These results and the experiments involving N-acetyl cysteine (antioxidant), Cyclosporin A (mitochondrial protector), and LY294002 (Akt inhibitor) suggest that PD prevents MGO-induced HUVEC apoptosis, at least in part, through inhibiting oxidative stress, maintaining mitochondrial function, and activating Akt pathway. All of these data indicate the potential application of PD for the treatment of diabetic vascular complication.

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