scholarly journals oxLDL-mediated cellular senescence is associated with increased NADPH oxidase p47phox recruitment to caveolae

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Jing Wang ◽  
Yuzhi Bai ◽  
Xia Zhao ◽  
Jing Ru ◽  
Ning Kang ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Clinical Intervention ◽  
Ros Generation ◽  
Ros Production ◽  
Caveolin 1 ◽  
Cellular Ageing ◽  
Vascular Endothelia ◽  
Membrane Target ◽  
High Degree ◽  
Atherosclerotic Changes

Atherosclerosis develops as a consequence of inflammation and cell senescence. In critical factors involved in the atherosclerotic changes, reactive oxygen species (ROS) generation is considered a leading cause. While NADPH oxidases, particularly NOX2, are the main sources of ROS, how they are regulated in the disease is incompletely understood. In addition, how caveolae, the membrane structure implicated in oxLDL deposition under vascular endothelia, is involved in the oxLDL-mediated ROS production remains mostly elusive. We report here that macrophages exposed to oxLDL up-regulate its caveolin-1 expression, and the latter in turn up-regulates NOX2 p47phox level. This combination effect results in increased cellular senescence. Interestingly, oxLDL treatment causes the p47phox residing in the cytosol to translocate to the caveolae. Immunoprecipitation assays confirms that cavelin-1 is in high degree association with p47phox. These results suggest caveolin-1 may serve as the membrane target for p47phox and as a switch for ROS production following oxLDL exposure. Our results reveal a previously unknown molecular event in oxLDL-mediated cellular ageing, and may provide a target for clinical intervention for atherosclerosis.

scholarly journals Reactive Oxygen Species in Host Plant Are Required for an Early Defense Response against Attack of Stagonospora nodorum Berk. Necrotrophic Effectors SnTox

Plants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1586
Author(s):  
Svetlana Veselova ◽  
Tatyana Nuzhnaya ◽  
Guzel Burkhanova ◽  
Sergey Rumyantsev ◽  
Igor Maksimov
Keyword(s):  
Reactive Oxygen Species ◽  
Early Stage ◽  
Reactive Oxygen ◽  
Triticum Aestivum L ◽  
Redox Status ◽  
Stagonospora Nodorum ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Necrotrophic Effectors

Reactive oxygen species (ROS) play a central role in plant immune responses. The most important virulence factors of the Stagonospora nodorum Berk. are multiple fungal necrotrophic effectors (NEs) (SnTox) that affect the redox-status and cause necrosis and/or chlorosis in wheat lines possessing dominant susceptibility genes (Snn). However, the effect of NEs on ROS generation at the early stages of infection has not been studied. We studied the early stage of infection of various wheat genotypes with S nodorum isolates -Sn4VD, SnB, and Sn9MN, carrying a different set of NE genes. Our results indicate that all three NEs of SnToxA, SnTox1, SnTox3 significantly contributed to cause disease, and the virulence of the isolates depended on their differential expression in plants (Triticum aestivum L.). The Tsn1–SnToxA, Snn1–SnTox1and Snn3–SnTox3 interactions played an important role in inhibition ROS production at the initial stage of infection. The Snn3–SnTox3 inhibited ROS production in wheat by affecting NADPH-oxidases, peroxidases, superoxide dismutase and catalase. The Tsn1–SnToxA inhibited ROS production in wheat by affecting peroxidases and catalase. The Snn1–SnTox1 inhibited the production of ROS in wheat by mainly affecting a peroxidase. Collectively, these results show that the inverse gene-for gene interactions between effector of pathogen and product of host sensitivity gene suppress the host’s own PAMP-triggered immunity pathway, resulting in NE-triggered susceptibility (NETS). These results are fundamentally changing our understanding of the development of this economical important wheat disease.

Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor

2013 ◽  
Vol 305 (2) ◽  
pp. H155-H162 ◽  
Author(s):  
Sayoko Ogura ◽  
Tatsuo Shimosawa ◽  
ShengYu Mu ◽  
Takashi Sonobe ◽  
Fumiko Kawakami-Mori ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Ros Generation ◽  
Low Density ◽  
Ros Production ◽  
Oxidized Low Density Lipoprotein

Chronic hypoxia is one of the main causes of pulmonary hypertension (PH) associated with ROS production. Lectin-like oxidized low-density lipoprotein receptor (LOX)-1 is known to be an endothelial receptor of oxidized low-density lipoprotein, which is assumed to play a role in the initiation of ROS generation. We investigated the role of LOX-1 and ROS generation in PH and vascular remodeling in LOX-1 transgenic (TG) mice. We maintained 8- to 10-wk-old male LOX-1 TG mice and wild-type (WT) mice in normoxia (room air) or hypoxia (10% O2 chambers) for 3 wk. Right ventricular (RV) systolic pressure (RVSP) was comparable between the two groups under normoxic conditions; however, chronic hypoxia significantly increased RVSP and RV hypertrophy in LOX-1 TG mice compared with WT mice. Medial wall thickness of the pulmonary arteries was significantly greater in LOX-1 TG mice than in WT mice. Furthermore, hypoxia enhanced ROS production and nitrotyrosine expression in LOX-1 TG mice, supporting the observed pathological changes. Administration of the NADPH oxidase inhibitor apocynin caused a significant reduction in PH and vascular remodeling in LOX-1 TG mice. Our results suggest that LOX-1-ROS generation induces the development and progression of PH.

Abstract 520: High-density Lipoprotein Inhibits Human M1 Macrophage Polarisation through the Redistribution of Caveolin-1

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Man K Lee ◽  
Xiao-Lei Moore ◽  
Yi Fu ◽  
Annas Al-sharea ◽  
Dragana Dragoljeic ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cholesterol Efflux ◽  
Human Macrophage ◽  
Ros Production ◽  
Oxygen Species ◽  
M1 Macrophages ◽  
Macrophage Polarisation ◽  
Caveolin 1 ◽  
M1 Phenotype ◽  
M2 Phenotype

Macrophages play a critical role in the development and progression of atherosclerosis. Depending on their surrounding milieu, macrophages can adopt a wide range of functional phenotypes; pro-inflammatory (M1) and pro-resolving (M2). HDL has many cardio-protective properties including potent anti-inflammatory effects, largely through the removal of cholesterol from cells. It is currently not known if this extends to influencing human macrophage phenotypes. Thus, we aimed to investigate the effect of HDL on human macrophage polarisation. Human blood monocyte-derived macrophages were induced to either an M1-phenotype by incubation with LPS and IFN-γ or to an M2-phenotype with IL-4. Macrophages were differentiated in the presence or absence of human HDL and their phenotypes were characterised using cell surface markers, reactive oxygen species (ROS) production by flow cytometry, and mRNA expression by real-time PCR. Downstream signalling pathways were also explored. We discovered that HDL inhibited the induction to M1 as evidenced by a decrease in cell surface marker expression; CD192 and CD64. This was accompanied by a decreased expression of M1-associated inflammatory genes TNF-α, IL-6 and MCP-1. However, HDL had no effect on induction to the M2 phenotype. Similarly, methyl-beta-cyclodextrin (MβCD), a non-specific cholesterol acceptor was also able to suppress M1 induction suggesting cholesterol efflux is important in this process. Further we found that HDL decreased membrane caveolin-1 in M1 macrophages and redistributed it intracellularly. The requirement of caveolin-1 was revealed as bone marrow-derived macrophages from Cav-1-/- mice continued to differentiate into M1 despite the addition of HDL. Moreover, we demonstrated a decrease in STAT3 and ERK1/2 phosphorylation in M1 macrophages treated with HDL, suggesting cholesterol efflux inhibits the STAT3s and MAPKs during induction to the M1 phenotype. Finally, we found that HDL also inhibited M1 function; with reduced reactive oxygen species (ROS) production. We provide evidence that HDL reduces macrophage induction to the inflammatory M1 phenotype, but not M2, via cellular redistribution of caveolin-1 and inactivation of STAT3 and ERK1/2 signalling pathway.

scholarly journals Another Facet to the Anticancer Response to Lamellarin D: Induction of Cellular Senescence through Inhibition of Topoisomerase I and Intracellular Ros Production

Marine Drugs ◽  
2014 ◽  
Vol 12 (2) ◽  
pp. 779-798 ◽  
Author(s):  
Caroline Ballot ◽  
Alain Martoriati ◽  
Manel Jendoubi ◽  
Sébastien Buche ◽  
Pierre Formstecher ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Topoisomerase I ◽  
Ros Production ◽  
Intracellular Ros ◽  
Anticancer Response

scholarly journals Diabetes potentiates ROS production in granulocytes from patients with chronic kidney disease

2021 ◽  
Vol 9 (1) ◽  
pp. 9-14
Author(s):  
Jose Augusto Nogueira-Machado ◽  
Gabriela Rossi Ferreira ◽  
Caroline Maria Oliveira Volpe ◽  
Pedro Henrique Villar-Delfino ◽  
Fabiana Rocha Silva
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nadph Oxidase ◽  
Ros Generation ◽  
Ros Production ◽  
Clinical Prognosis ◽  
Before And After ◽  
Healthy Control ◽  
Toll Receptor

Background: Type 2 diabetes (DM2) and chronic kidney disease (CKD) are inflammatory pathologies. Diabetes is characterized by hyperglycemia and CKD by the gradual and irreversible loss of kidney function. Both diseases develop oxidative stress, and reactive oxygen species (ROS) play a pivotal role in the pathogenesis. This study aimed to determine ROS production by granulocytes from renal patients (CKD) with or without diabetes. Methods: Granulocytes from patients with DM2, CKD, CKD-DM2, and healthy controls were purified using the Ficoll-Hypaque gradient method. Granulocyte ROS generation in the absence or the presence of PDB (an activator of NADPH-oxidase) or Concanavalin A (Toll- receptor 3,9 activator) was evaluated in a luminol-dependent chemiluminescence method. The cell-free DNA in the serum of DM2, CKD, and CKD-DM2 patients was measured by the fluorescence method before and after hemodialysis. Results: Our results show a significant increase in ROS production by granulocytes from patients with CKD, DM2, and CKD-DM2 compared to healthy control (p<0.05). CKD-DM2 group produced the most significant ROS levels with or without NADPH-oxidase activation. ROS production showed a significant increase in the presence of ConA. In contrast, mitochondrial (internal) ROS showed a different ROS response. DNA extrusion was higher in the CKD-DM2 group after hemodialysis suggesting cell death. Conclusion: The results demonstrated that CKD-DM2 patients produced high ROS generation levels and increased DNA extrusion after hemodialysis. It may suggest that CKD-DM2 disease is more severe and has a worse clinical prognosis.

scholarly journals Potential mechanisms of quantitative resistance to Leptosphaeria maculans (blackleg) on cotyledons of canola (Brassica napus)

2020 ◽  
Author(s):  
Michelle Hubbard ◽  
Chun Zhai ◽  
Gary Peng
Keyword(s):  
Signal Transduction ◽  
Cell Death ◽  
Fluorescent Protein ◽  
Quantitative Resistance ◽  
Leptosphaeria Maculans ◽  
Small Gtpases ◽  
Ros Generation ◽  
Ros Production ◽  
Potential Marker ◽  
Starting Point

Abstract Background: Blackleg disease, caused by Leptosphaeria maculans (Lm), can lead to significant losses of canola/rapeseed crops. Growing resistant canola cultivars can be an effective and environmentally friendly way to manage blackleg. Major resistance genes may stop infection, but can also be rapidly overcome by shifts in pathogen population towards virulence. Thus, using race-nonspecific or quantitative resistance (QR) is of interest because it is potentially more durable. However, the mechanisms and genes underlying QR are mostly unknown. In this study, we explored QR in “74‑44 BL”, a Canadian canola cultivar carrying a moderate level of race nonspecific resistance, based on cotyledon inoculation (Supple. Fig.1) . The susceptible cultivar “Westar” was used as a control. Lesions developed more slowly on 74-44BL than on Westar. We used RNA-Seq to identify genes and gene functions putatively involved in the QR. Results: Relative to inoculated Westar, some of the B. napus genes that were differentially expressed strongly in inoculated 74-44 BL included those putatively involved in programmed cell death (PCD), reactive oxygen species (ROS) generation, signal transduction and/or intracellular endomembrane transport. Examples included genes annotated as a Bax inhibitor 1, a development/cell death (DCD) domain containing proteinases and peptidases, all of which could play a role in PCD and a zinc-finger Sec23/Sec24 and five small GTPases likely involved in endoplasmic reticulum (ER) to Golgi vesicle traffic and/or signal transduction. Further experiments, however, did not confirm changes in genomic DNA degradation, a potential marker for PCD, between the two cultivars. In addition, infection progression in cotyledons was not altered by applying protease inhibitors directly to cotyledons. Additional testing was done using green fluorescent protein (GFP)-tagged Lm for cotyledon colonization as well as ROS production, in relation to the lesion development. The results showed that ROS production occurred beyond the area colonized by Lm hyphae in 74-44 BL.Conclusions: ROS may also be involved in signal transduction and/or intracellular endomembrane transport. These results provide a starting point for a better understanding of the mechanisms behind QR against Lm in canola and developing new host-resistance strategies for management of blackleg.

scholarly journals Effect of the Antioxidant Lipoic Acid in Aortic Phenotype in a Marfan Syndrome Mouse Model

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Maria C. Guido ◽  
Victor Debbas ◽  
Vera M. Salemi ◽  
Elaine R. Tavares ◽  
Thayna Meirelles ◽  
...  
Keyword(s):  
Mouse Model ◽  
Marfan Syndrome ◽  
Lipoic Acid ◽  
Elastic Fiber ◽  
Aortic Aneurysms ◽  
Ros Generation ◽  
Ros Production ◽  
Aortic Dilation ◽  
Advanced Stages ◽  
Aortic Remodeling

Marfan syndrome (MFS) cardiovascular manifestations such as aortic aneurysms and cardiomyopathy carry substantial morbidity/mortality. We investigated the effects of lipoic acid, an antioxidant, on ROS production and aortic remodeling in a MFS mgΔloxPneo mouse model. MFS and WT (wild-type) 1-month-old mice were allocated to 3 groups: untreated, treated with losartan, and treated with lipoic acid. At 6 months old, echocardiography, ROS production, and morphological analysis of aortas were performed. Aortic ROS generation in 6-month-old MFS animals was higher at advanced stages of disease in MFS. An unprecedented finding in MFS mice analyzed by OCT was the occurrence of focal inhomogeneous regions in the aortic arch, either collagen-rich extremely thickened or collagen-poor hypotrophic regions. MFS animals treated with lipoic acid showed markedly reduced ROS production and lower ERK1/2 phosphorylation; meanwhile, aortic dilation and elastic fiber breakdown were unaltered. Of note, lipoic acid treatment associated with the absence of focal inhomogeneous regions in MFS animals. Losartan reduced aortic dilation and elastic fiber breakdown despite no change in ROS generation. In conclusion, oxidant generation by itself seems neutral with respect to aneurysm progression in MFS; however, lipoic acid-mediated reduction of inhomogeneous regions may potentially associate with less anisotropy and reduced chance of dissection/rupture.

Abstract 19967: Differential Roles of the NADPH-Oxidase 1 and 2 in Platelet Activation and Thrombosis

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Michael K Delaney ◽  
Kyungho Kim ◽  
Brian Estevez ◽  
Aleksandra Stojanovic-Terpo ◽  
Bo Shen ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Platelet Activation ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
General Role ◽  
Glycoprotein Vi ◽  
Activation Pathways

Objective: Reactive oxygen species (ROS) generated from activated platelets is known to regulate platelet activation. However, it remains unclear whether and how different isoforms of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidases (NOXs) play roles in different platelet activation pathways. Here we investigated the role of NOX1 and NOX2 in different platelet activation pathways using NOX1 and NOX2 knockout mice. Approach and Results: NOX1-/- platelets showed selective defects in G protein coupled receptor (GPCR)-mediated platelet activation induced by thrombin, protease-activated receptor 4 agonist peptide (PAR4AP) and thromboxane A2 analog U46619, but was not affected in platelet activation induced by collagen-related peptide (CRP), a glycoprotein VI (GPVI) agonist. In contrast, NOX2-/- platelets showed potent inhibition of CRP-induced platelet activation, and also showed partial inhibition of thrombin-induced platelet aggregation and secretion. Consistently, production of reactive oxygen species (ROS) was inhibited in NOX1-/- platelets stimulated with thrombin, but not CRP, whereas NOX2-/- platelets showed reduced ROS generation induced by CRP or thrombin. Interestingly, laser-induced arterial thrombosis was impaired in NOX2-/- mice, and in thrombocytopenic mice transfused with NOX2-/- platelets, suggesting an important role for NOX2-dependent platelet ROS production in the laser-induced injury model of thrombosis. Conclusions: NOX1 and NOX2 play differential roles in different platelet activation pathways: NOX1 mediates GPCR-mediated ROS production and platelet activation, whereas NOX2 plays a general role in GPVI- and GPCR-induced ROS production and platelet activation in vitro , and in laser-induced thrombosis in vivo .

Abstract P241: Calpain-1 Is Increased in Mitochondria and Contributes to Mitochondrial ROS Generation in High Glucose--Stimulated Endothelial Cells and Endothelial Dysfunction in Mouse Models of Diabetes

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Qing Zhao ◽  
Futian Tang ◽  
Limei Shan ◽  
Inga Cepinskas ◽  
Gedas Cepinskas ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
High Glucose ◽  
Aortic Ring ◽  
Ros Generation ◽  
Type I ◽  
Ros Production ◽  
Diabetic Mice ◽  
Calpain Activity ◽  
Over Expression ◽  
Mitochondrial Ros

Objectives: Elevated levels of reactive oxygen species (ROS) are the initial source of endothelial dysfunction in diabetes. Calpain has been implicated in diabetic vascular complications. The present study was to investigate the role of calpain in mitochondrial ROS generation in endothelial cells and vascular dysfunction in diabetic mice. Methods: Endothelial cells cultured from human umbilical vein (HUVEC) were stimulated with high glucose. Calpain activity and protein were determined in mitochondria of HUVEC. Intracellular and mitochondrial ROS generation as well as apoptosis were measured. Type I diabetic OVE 26 mice and type II diabetic db/db mice with calpastatin over-expression (OVE26/CAST and db/db-CAST) were generated, respectively. Type I diabetes was also induced in both wild-type and Tg-CAST mice by injection of streptozocin (STZ). The endothelium-dependent relaxation of aortic ring was measured. Results: High glucose significantly increased calpain-1 protein, calpain activity and ROS generation in mitochondria of HUVEC. Pharmacological inhibition of calpain or over-expression of calpastatin abrogated high glucose-induced intracellular ROS production, mitochondrial ROS generation and apoptosis in HUVEC. Incubation of isolated mitochondria with calpain-1 protein significantly induced its ROS generation and the membrane potential. In diabetic mice, calpain activity was induced in aortic vessels, which correlated with an increase in ROS production and protein tyrosine nitration. Over-expression of calpastatin prevented calpain activity, reduced ROS production and inhibited protein tyrosine nitration in diabetic mice. Aortic ring segments from diabetic mice exhibited a significant reduction in vascular relaxation to acetylcholine, which was reversed by over-expression of calpastatin in Tg-CAST, OVE26/CAST and db/db-CAST mice. Conclusions: This study has demonstrated a novel role of calpain in mitochondrial ROS generation, which contributes to apoptosis in endothelial cells during hyperglycemia. Thus, over-expression of calpastatin inhibits reduces ROS production and ameliorates endothelium-dependent vascular dysfunction in mouse models of diabetes.

Abstract P311: Blocking Succinate Release Enhances Mitochondrial Reactive Oxygen Species Generation And Worsens Ischemia-reperfusion Injury

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Alexander S Milliken ◽  
Sergiy M Nadtochiy ◽  
Paul S Brookes
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen Species Generation ◽  
Ros Generation ◽  
Ros Production ◽  
Succinate Oxidation ◽  
Fluorescence Measurements ◽  
Mitochondrial Ros ◽  
The Impact ◽  
Infarction Heart

Succinate is a metabolite that plays a central role in ischemia-reperfusion (IR) injury,which is relevant to myocardial infarction (heart attack) and stroke. Succinateaccumulates during ischemia and is rapidly consumed at reperfusion driving reactiveoxygen species (ROS) generation at complex-I (Cx-I) and III of the mitochondrial electrontransport chain. This ROS production triggers cell-death, leading to tissue necrosis.Although succinate oxidation has been extensively studied and exploited as a noveltherapeutic target, only 1/3 of the succinate accumulated in ischemia is oxidized atreperfusion, with the remaining 2/3 being released from the cell via monocarboxylatetransporter 1 (MCT1). Extracellular succinate is thought to be pro-inflammatory, and ithas been proposed that preventing succinate release may be therapeutically beneficial.To determine the impact of preventing succinate release on IR injury, we comparedfunctional recovery (i.e. rate x pressure product, RPP) and infarction (i.e. tissue necrosis)of Langendorff perfused mouse hearts treated with an MCT1 inhibitor, AR-C155858,versus vehicle control. This revealed that succinate retention worsens IR injury (i.e.increased infarction and decreased functional recovery) likely due to increased ROS. Totest this hypothesis, we utilized a Langendorff apparatus positioned within aspectrofluorimeter, which permits real-time fluorescence measurements in beatingmouse hearts. Using the mitochondria targeted superoxide probe, MitoSOX red tomeasure ROS production at reperfusion + AR-C155858, demonstrated that succinateretention leads to enhanced mitochondrial ROS generation at the onset of reperfusion.Overall, these results suggest that inhibiting succinate release in the context of IR injurymay not be a viable therapeutic approach, regardless of any downstream anti-inflammatory effects.

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