Protection of the vascular endothelium in experimental situations

Protection of the vascular endothelium in experimental situationsOne of the factors proposed as mediators of vascular dysfunction observed in diabetes is the increased generation of reactive oxygen species (ROS). This provides support for the use of antioxidants as early and appropriate pharmacological intervention in the development of late diabetic complications. In streptozotocin (STZ)-induced diabetes in rats we observed endothelial dysfuction manifested by reduced endothelium-dependent response to acetylcholine of the superior mesenteric artery (SMA) and aorta, as well as by increased endothelaemia. Changes in endothelium-dependent relaxation of SMA were induced by injury of the nitric oxide radical (·NO)-signalling pathway since the endothelium-derived hyperpolarising factor (EDHF)-component of relaxation was not impaired by diabetes. The endothelial dysfunction was accompanied by decreased ·NO bioavailabity as a consequence of reduced activity of eNOS rather than its reduced expression. The results obtained using the chemiluminiscence method (CL) argue for increased oxidative stress and increased ROS production. The enzyme NAD(P)H-oxidase problably participates in ROS production in the later phases of diabetes. Oxidative stress was also connected with decreased levels of reduced glutathione (GSH) in the early phase of diabetes. After 10 weeks of diabetes, adaptational mechanisms probably took place because GSH levels were not changed compared to controls. Antioxidant properties of SMe1EC2 foundin vitrowere partly confirmedin vivo.Administration of SMe1EC2 protected endothelial function. It significantly decreased endothelaemia of diabetic rats and improved endothelium-dependent relaxation of arteries, slightly decreased ROS-production and increased bioavailability of ·NO in the aorta. Further studies with higher doses of SMe1EC2 may clarify the mechanism of its endothelium-protective effectin vivo.

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Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

International Journal of Molecular Sciences ◽

10.3390/ijms22041514 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1514 ◽

Cited By ~ 1

Author(s):

Akihiro Yachie

Keyword(s):

Oxidative Stress ◽

Animal Models ◽

Heme Oxygenase ◽

Inflammatory Diseases ◽

Cell Types ◽

Pharmacological Intervention ◽

Heme Oxygenase 1 ◽

Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

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Vascular Dysfunction Induced by Mercury Exposure

International Journal of Molecular Sciences ◽

10.3390/ijms20102435 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2435 ◽

Cited By ~ 4

Author(s):

Tetsuya Takahashi ◽

Takayoshi Shimohata

Keyword(s):

Oxidative Stress ◽

Vascular Dysfunction ◽

Brain Parenchyma ◽

Transport Systems ◽

Mehg Exposure ◽

In Vivo Models ◽

The Central Nervous System ◽

The Brain

Methylmercury (MeHg) causes severe damage to the central nervous system, and there is increasing evidence of the association between MeHg exposure and vascular dysfunction, hemorrhage, and edema in the brain, but not in other organs of patients with acute MeHg intoxication. These observations suggest that MeHg possibly causes blood–brain barrier (BBB) damage. MeHg penetrates the BBB into the brain parenchyma via active transport systems, mainly the l-type amino acid transporter 1, on endothelial cell membranes. Recently, exposure to mercury has significantly increased. Numerous reports suggest that long-term low-level MeHg exposure can impair endothelial function and increase the risks of cardiovascular disease. The most widely reported mechanism of MeHg toxicity is oxidative stress and related pathways, such as neuroinflammation. BBB dysfunction has been suggested by both in vitro and in vivo models of MeHg intoxication. Therapy targeted at both maintaining the BBB and suppressing oxidative stress may represent a promising therapeutic strategy for MeHg intoxication. This paper reviews studies on the relationship between MeHg exposure and vascular dysfunction, with a special emphasis on the BBB.

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The Protective Roles of Estrogen Receptor β in Renal Calcium Oxalate Crystal Formation via Reducing the Liver Oxalate Biosynthesis and Renal Oxidative Stress-Mediated Cell Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/5305014 ◽

2019 ◽

Vol 2019 ◽

pp. 1-17 ◽

Cited By ~ 3

Author(s):

Wei Zhu ◽

Zhijian Zhao ◽

Fu-Ju Chou ◽

Li Zuo ◽

Tongzu Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Estrogen Receptor ◽

Nadph Oxidase ◽

Calcium Oxalate ◽

Cell Lines ◽

Ros Production ◽

Crystal Deposition ◽

Caox Crystal

Females develop kidney stones less frequently than males do. However, it is unclear if this gender difference is related to altered estrogen/estrogen receptor (ER) signaling. Here, we found that ER beta (ERβ) signals could suppress hepatic oxalate biosynthesis via transcriptional upregulation of the glyoxylate aminotransferase (AGT1) expression. Results from multiple in vitro renal cell lines also found that ERβ could function via suppressing the oxalate-induced injury through increasing the reactive oxygen species (ROS) production that led to a decrease of the renal calcium oxalate (CaOx) crystal deposition. Mechanism study results showed that ERβ suppressed oxalate-induced oxidative stress via transcriptional suppression of the NADPH oxidase subunit 2 (NOX2) through direct binding to the estrogen response elements (EREs) on the NOX2 5′ promoter. We further applied two in vivo mouse models with glyoxylate-induced renal CaOx crystal deposition and one rat model with 5% hydroxyl-L-proline-induced renal CaOx crystal deposition. Our data demonstrated that mice lacking ERβ (ERβKO) as well as mice or rats treated with ERβ antagonist PHTPP had increased renal CaOx crystal deposition with increased urinary oxalate excretion and renal ROS production. Importantly, targeting ERβ-regulated NOX2 with the NADPH oxidase inhibitor, apocynin, can suppress the renal CaOx crystal deposition in the in vivo mouse model. Together, results from multiple in vitro cell lines and in vivo mouse/rat models all demonstrate that ERβ may protect against renal CaOx crystal deposition via inhibiting the hepatic oxalate biosynthesis and oxidative stress-induced renal injury.

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Aspirin Eugenol Ester Protects Vascular Endothelium From Oxidative Injury by the Apoptosis Signal Regulating Kinase-1 Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.588755 ◽

2020 ◽

Vol 11 ◽

Author(s):

Mei-Zhou Huang ◽

Zhen-Dong Zhang ◽

Ya-Jun Yang ◽

Xi-Wang Liu ◽

Zhe Qin ◽

...

Keyword(s):

Oxidative Stress ◽

Vascular Endothelium ◽

Cell Apoptosis ◽

Oxidative Injury ◽

Vital Role ◽

Stress Effect ◽

Antioxidative Stress ◽

Aspirin Eugenol Ester

Aspirin eugenol ester (AEE) is a new potential pharmaceutical compound possessing anti-inflammatory, anti-cardiovascular disease, and antioxidative stress activity. The pharmacological activities of AEE are partly dependent on its regulation of cell apoptosis. However, it is still unclear how AEE inhibits cell apoptosis on the basis of its antioxidative stress effect. This study aimed to reveal the vascular antioxidative mechanism of AEE in response to H2O2-induced oxidative stress in HUVECs and paraquat-induced oxidative stress in rats. In the different intervention groups of HUVECs and rats, the expression of ASK1, ERK1/2, SAPK/JNK, and p38 and the phosphorylation levels of ERK1/2, SAPK/JNK, and p38 were measured. The effects of ASK1 and ERK1/2 on the anti-apoptotic activity of AEE in the oxidative stress model were probed using the corresponding inhibitors ASK1 and ERK1/2. The results showed that in the HUVECs, 200 μM H2O2 treatment significantly increased the phosphorylation of SAPK/JNK and the level of ASK1 but decreased the phosphorylation of ERK1/2, while in the HUVECs pretreated with AEE, the H2O2-induced changes were significantly ameliorated. The findings were observed in vitro and in vivo. Moreover, inhibition of ASK1 and ERK1/2 showed that ASK1 plays a vital role in the protective effect of AEE on H2O2-induced apoptosis. All findings suggested that AEE protects the vascular endothelium from oxidative injury by mediating the ASK1 pathway.

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Antioxidant supplementation slows telomere shortening in free-living white stork chicks

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2019.1917 ◽

2020 ◽

Vol 287 (1918) ◽

pp. 20191917 ◽

Cited By ~ 6

Author(s):

Javier Pineda-Pampliega ◽

Amparo Herrera-Dueñas ◽

Ellis Mulder ◽

José I. Aguirre ◽

Ursula Höfle ◽

...

Keyword(s):

Oxidative Stress ◽

Antioxidant Properties ◽

White Stork ◽

Control Treatment ◽

Antioxidant Treatment ◽

Telomere Attrition ◽

Final Sample ◽

Shortening Rate

Telomere length (TL) and shortening is increasingly shown to predict variation in survival and lifespan, raising the question of what causes variation in these traits. Oxidative stress is well known to accelerate telomere attrition in vitro , but its importance in vivo is largely hypothetical. We tested this hypothesis experimentally by supplementing white stork ( Ciconia ciconia ) chicks with antioxidants. Individuals received either a control treatment, or a supply of tocopherol (vitamin E) and selenium, which both have antioxidant properties. The antioxidant treatment increased the concentration of tocopherol for up to two weeks after treatment but did not affect growth. Using the telomere restriction fragment technique, we evaluated erythrocyte TL and its dynamics. Telomeres shortened significantly over the 21 days between the baseline and final sample, independent of sex, mass, size and hatching order. The antioxidant treatment significantly mitigated shortening rate of average TL (−31% in shorter telomeres; percentiles 10th, 20th and 30th). Thus, our results support the hypothesis that oxidative stress shortens telomeres in vivo .

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ROS dependence of cyclooxygenase-2 induction in rats subjected to unilateral ureteral obstruction

AJP Renal Physiology ◽

10.1152/ajprenal.00352.2013 ◽

2014 ◽

Vol 306 (2) ◽

pp. F259-F270 ◽

Cited By ~ 26

Author(s):

Martin Østergaard ◽

Michael Christensen ◽

Line Nilsson ◽

Inge Carlsen ◽

Jørgen Frøkiær ◽

...

Keyword(s):

Oxidative Stress ◽

Ureteral Obstruction ◽

Oxidase Inhibitor ◽

Unilateral Ureteral Obstruction ◽

Tubular Damage ◽

Ros Production ◽

Cox 2 ◽

And Oxidative Stress

Oxidative stress resulting from unilateral ureteral obstruction (UUO) may be aggravated by increased production of ROS. Previous studies have demonstrated increased cyclooxygenase (COX)-2 expression in renal medullary interstitial cells (RMICs) in response to UUO. We investigated, both in vivo and in vitro, the role of ROS in the induction of COX-2 in rats subjected to UUO and in RMICs exposed to oxidative and mechanical stress. Rats subjected to 3-day UUO were treated with two mechanistically distinct antioxidants, the NADPH oxidase inhibitor diphenyleneiodonium (DPI) and the complex I inhibitor rotenone (ROT), to interfere with ROS production. We found that UUO-mediated induction of COX-2 in the inner medulla was attenuated by both antioxidants. In addition, DPI and ROT reduced tubular damage and oxidative stress after UUO. Moreover, mechanical stretch induced COX-2 and oxidative stress in RMICs. Likewise, RMICs exposed to H2O2 as an inducer of oxidative stress showed increased COX-2 expression and activity, both of which were reduced by DPI and ROT. Similarly, ROS production, which was increased after exposure of RMICs to H2O2, was also reduced by DPI and ROT. Furthermore, oxidative stress-induced phosphorylation of ERK1/2 and p38 was blocked by both antioxidants, and inhibition of ERK1/2 and p38 attenuated the induction of COX-2 in RMICs. Notably, COX-2 inhibitors further exacerbated the oxidative stress level in H2O2-exposed RMICs. We conclude that oxidative stress as a consequence of UUO stimulates COX-2 expression through the activation of multiple MAPKs and that the induction of COX-2 may exert a cytoprotective function in RMICs.

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Synthesis, Characterization of Pyrano-[2,3-c]-Pyrazoles Derivatives and Determination of Their Antioxidant Activities

Iranian Jornal of Toxicology ◽

10.32598/ijt.15.3.798.1 ◽

2021 ◽

Vol 15 (3) ◽

pp. 175-194

Author(s):

Boutaina Addoum ◽

◽

Bouchra El khalfi ◽

Mohamed Idiken ◽

Souraya Sakoui ◽

...

Keyword(s):

Oxidative Stress ◽

High Performance ◽

Antioxidant Activities ◽

Antioxidant Properties ◽

Model Organism ◽

Biologically Active ◽

Strong Activity ◽

Nitrative Stress

Background: Antioxidants are developed to assist the immune system and overcome oxidative stress, the aggression of cellular constituents due to imbalance between reactive oxygen species and the inner antioxidant system. The main objective of this study was to search for new and potent antioxidants to protect humans against diseases associated with oxidative stress. Methods: In this study, three pyrano-[2,3-c]-pyrazole derivatives were synthesized via Multicomponent Reaction (MCR) approach and were characterized, using a melting point, High-Performance Liquid Chromatography (HPLC), and spectroscopic analyses (IR; 1H-NMR; 13C-NMR). All of the generated compounds were screened for their antioxidant properties in vivo, using ciliate “Tetrahymena” as a model organism exposed to oxidative and nitrative stress. They were then studied in vitro by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Results: The results demonstrated that the three compounds (5a, b, c) are biologically active and possess potent antioxidant activities, especially the 5a and 5b derivatives. On the other hand, the in vitro bioassays revealed that the 5a derivative possessed a significant antioxidant activity much greater than ascorbic acid. Accordingly, the in silico data are consistent with the experimental data. Conclusion: These findings confirmed the potent antioxidant property of the synthesized compounds, providing us with new inspiration and challenges to design a library of pharmaceutical compounds with strong activity and low toxicity in the future.

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Dextromethorphan Reduces Oxidative Stress and Inhibits Uremic Artery Calcification

International Journal of Molecular Sciences ◽

10.3390/ijms222212277 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12277

Author(s):

En-Shao Liu ◽

Nai-Ching Chen ◽

Tzu-Ming Jao ◽

Chien-Liang Chen

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Vascular Calcification ◽

Wistar Rats ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Oxidase Inhibitor ◽

In Vivo Studies ◽

Ros Production

Medial vascular calcification has emerged as a key factor contributing to cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs) with osteogenic transdifferentiation play a role in vascular calcification. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors reduce reactive oxygen species (ROS) production and calcified-medium–induced calcification of VSMCs. This study investigates the effects of dextromethorphan (DXM), an NADPH oxidase inhibitor, on vascular calcification. We used in vitro and in vivo studies to evaluate the effect of DXM on artery changes in the presence of hyperphosphatemia. The anti-vascular calcification effect of DXM was tested in adenine-fed Wistar rats. High-phosphate medium induced ROS production and calcification of VSMCs. DXM significantly attenuated the increase in ROS production, the decrease in ATP, and mitochondria membrane potential during the calcified-medium–induced VSMC calcification process (p < 0.05). The protective effect of DXM in calcified-medium–induced VSMC calcification was not further increased by NADPH oxidase inhibitors, indicating that NADPH oxidase mediates the effect of DXM. Furthermore, DXM decreased aortic calcification in Wistar rats with CKD. Our results suggest that treatment with DXM can attenuate vascular oxidative stress and ameliorate vascular calcification.

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The Role of Signaling Pathways of Inflammation and Oxidative Stress in Development of Senescence and Aging Phenotypes in Cardiovascular Disease

Cells ◽

10.3390/cells8111383 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1383 ◽

Cited By ~ 17

Author(s):

John Papaconstantinou

Keyword(s):

Oxidative Stress ◽

Cardiovascular Diseases ◽

P38 Mapk ◽

Mapk Pathway ◽

Pharmacological Intervention ◽

Mapk Activity ◽

Chain Complexes ◽

Stress Signals

The ASK1-signalosome→p38 MAPK and SAPK/JNK signaling networks promote senescence (in vitro) and aging (in vivo, animal models and human cohorts) in response to oxidative stress and inflammation. These networks contribute to the promotion of age-associated cardiovascular diseases of oxidative stress and inflammation. Furthermore, their inhibition delays the onset of these cardiovascular diseases as well as senescence and aging. In this review we focus on whether the (a) ASK1-signalosome, a major center of distribution of reactive oxygen species (ROS)-mediated stress signals, plays a role in the promotion of cardiovascular diseases of oxidative stress and inflammation; (b) The ASK1-signalosome links ROS signals generated by dysfunctional mitochondrial electron transport chain complexes to the p38 MAPK stress response pathway; (c) the pathway contributes to the sensitivity and vulnerability of aged tissues to diseases of oxidative stress; and (d) the importance of inhibitors of these pathways to the development of cardioprotection and pharmaceutical interventions. We propose that the ASK1-signalosome regulates the progression of cardiovascular diseases. The resultant attenuation of the physiological characteristics of cardiomyopathies and aging by inhibition of the ASK1-signalosome network lends support to this conclusion. Importantly the ROS-mediated activation of the ASK1-signalosome p38 MAPK pathway suggests it is a major center of dissemination of the ROS signals that promote senescence, aging and cardiovascular diseases. Pharmacological intervention is, therefore, feasible through the continued identification of potent, non-toxic small molecule inhibitors of either ASK1 or p38 MAPK activity. This is a fruitful future approach to the attenuation of physiological aspects of mammalian cardiomyopathies and aging.

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Antioxidant Treatment Reverts Increased Arterial Basal Tone and Oxidative Stress in Nephrectomized (5/6) Hypertensive Rats

International Journal of Hypertension ◽

10.1155/2013/863067 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Rodrigo O. Marañón ◽

Claudio Joo Turoni ◽

Maria Sofia Karbiner ◽

Nicolas Salas ◽

Maria Peral de Bruno

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Vascular Dysfunction ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Basal Tone ◽

No Bioavailability

Nonischemic 5/6 nephrectomized rat (NefR) is a model of chronic kidney disease. However, little is known about vascular dysfunction and its relation with hypertension in NefR.Aims. To evaluate possible alterations of endothelial function, NO-bioavailability, and basal tone in aorta from NefR and the role of oxidative stress. Sprague Dawley rats were divided into sham rats (SR), NefR, and NefR treated with tempol (NefR-T). Mean arterial pressure (MAP) and renal function were determined. In isolated aortic rings the following was measured: 1-endothelial function, 2-basal tone, 3-NO levels, 4-membrane potential (MP), and 5-oxidative stress. NefR increased MAP (SR: 119 ± 4 mmHg;n=7; NefR: 169 ± 6;n=8;P<0.001). Tempol did not modify MAP (NefR-T: 168 ± 10;n=6;P<0.001). NefR showed endothelial dysfunction, increased basal tone and decreased NO levels (SR: 32 ± 2 nA;n=7, NefR: 10 ± 2;n=8;P<0.001). In both in vitro and in vivo tempol improves basal tone, NO levels, and MP. Oxidative stress in NefR was reverted in NefR-T. We described, for the first time, that aorta from NefR presented increased basal tone related to endothelial dysfunction and decreased NO-bioavailability. The fact that tempol improves NO-contents and basal tone, without decrease MAP, indicates that oxidative stress could be implicated early and independently to hypertension, in the vascular alterations.

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