Oxidative Stress and Vascular Inflammation

Abstract Objective Sepsis causes severe hypotension, accompanied by high mortality in the setting of septic shock. LEADER, SUSTAIN-6 and other clinical trials revealed cardioprotective and anti-inflammatory properties of GLP-1 analogs like Liraglutide (Lira). We already demonstrated improved survival by amelioration of disseminated intravasal coagulation (DIC) in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of the GLP-1 degrading enzyme dipeptidylpeptidase-4 (DPP-4). With the present study we aim to investigate the mechanism of protective effects of the GLP-1 analog Lira and the DPP4 inhibitor Linagliptin (Lina) in the clinically relevant sepsis model cecal ligation and puncture (CLP). Methods C57/BL6j and endothelial cell-specific GLP-1 receptor knockout mice (Cdh5crexGLP-1rfl/flmice) were used and sepsis was induced by cecal ligation and puncture (CLP). DPP4 inhibitor (Lina, 5mg/kg/d; 3 days) and GLP-1 analog (Lira, 200μg/kg/d; 3 days) were applied subcutaneously. Aortic vascular function was tested by isometric tension recording. Aorta and heart tissue was used for Western blotting, dot blot and qRT-PCR. Endogenous GLP-1 (7–36 and 9–36) and insulin was determined by ELISA. Blood samples were collected for examination of cell count, oxidative stress and glucose levels. Results Body temperature was increased by CLP and normalized by Lina and Lira. Sham- and Lira- but not Lina-treated septic mice showed low blood glucose levels compared to healthy controls. Acetylcholine-induced (endothelium-dependent) vascular relaxation in aorta was impaired by CLP. This was accompanied by vascular inflammation and elevation of IL-6, iNOS, ICAM-1, and TNF-alpha mRNA levels in aortic tissue. Vascular, cardiac and whole blood oxidative stress were increased by CLP. Furthermore, we detected higher levels of IL-6, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-NHE) in plasma of CLP animals. Lina and Lira reduced oxidative stress and vascular inflammation, which was accompanied by improved endothelial function. In addition, CLP treatment in endothelial specific knockout mice of the GLP-1r strongly induced mortality compared to WT mice, with the effect being strongest in the Lira-treated group. Conclusion The present study demonstrates that Lina (DPP4 inhibitor) and the GLP-1 analog Lira ameliorate sepsis-induced endothelial dysfunction by reduction of vascular inflammation and oxidative stress. Clinical trials like LEADER and SUSTAIN-6 proved that GLP-1 analogs like Lira have cardioprotective effects in T2DM patients. The present study, performed in a clinically relevant model of polymicrobial sepsis, reveals that the known cardioprotective effects of GLP-1 might be translated to other diseases which affect the cardiovascular system like sepsis, underlining the potent anti-inflammatory effects of GLP-1 analogs.

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GLP-1 Analog Liraglutide Improves Vascular Function in Polymicrobial Sepsis by Reduction of Oxidative Stress and Inflammation

Antioxidants ◽

10.3390/antiox10081175 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1175

Author(s):

Johanna Helmstädter ◽

Karin Keppeler ◽

Franziska Aust ◽

Leonie Küster ◽

Katie Frenis ◽

...

Keyword(s):

Oxidative Stress ◽

Vascular Function ◽

Vascular Inflammation ◽

Cecal Ligation ◽

Isometric Tension ◽

Polymicrobial Sepsis ◽

Dot Blot ◽

Markers Of Inflammation ◽

Anti Inflammatory ◽

And Oxidative Stress

Sepsis causes high mortality in the setting of septic shock. LEADER and other trials revealed cardioprotective and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) analogs like liraglutide (Lira). We previously demonstrated improved survival in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of GLP-1 degradation. Here we investigate the effects of Lira in the polymicrobial sepsis model of cecal ligation and puncture (CLP). C57BL/6J mice were intraperitoneally injected with Lira (200 µg/kg/d; 3 days) and sepsis induced by CLP after one day of GLP-1 analog treatment. Survival and body temperature were monitored. Aortic vascular function (isometric tension recording), protein expression (immunohistochemistry and dot blot) and gene expression (qRT-PCR) were determined. Endothelium-dependent relaxation in the aorta was impaired by CLP and correlated with markers of inflammation (e.g., interleukin 6 and inducible nitric oxide synthase) and oxidative stress (e.g., 3-nitrotyrosine) was higher in septic mice, all of which was almost completely normalized by Lira therapy. We demonstrate that the GLP-1 analog Lira ameliorates sepsis-induced endothelial dysfunction by the reduction of vascular inflammation and oxidative stress. Accordingly, the findings suggest that the antioxidant and anti-inflammatory effects of GLP-1 analogs may be a valuable tool to protect the cardiovascular system from dysbalanced inflammation in polymicrobial sepsis.

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CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice

Cardiovascular Research ◽

10.1093/cvr/cvx197 ◽

2017 ◽

Vol 114 (2) ◽

pp. 312-323 ◽

Cited By ~ 11

Author(s):

Sebastian Steven ◽

Mobin Dib ◽

Michael Hausding ◽

Fatemeh Kashani ◽

Matthias Oelze ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

High Fat Diet ◽

Immune Cell ◽

Vascular Inflammation ◽

Human Study ◽

Isometric Tension ◽

Wild Type ◽

High Fat ◽

Aorta Ascendens

Abstract Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and results Male wild type and CD40L−/− mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L expression, weight, leptin and lipids were increased, and endothelial dysfunction, oxidative stress and inflammation were more pronounced in wild type mice on a high fat diet, all of which was almost normalized by CD40L deficiency. Similar results were obtained in diabetic db/db mice with CD40/TRAF6 inhibitor (6877002) therapy. In a small human study higher serum sCD40L levels and an inflammatory phenotype were detected in the blood and Aorta ascendens of obese patients (body mass index > 35) that underwent by-pass surgery. Conclusion CD40L controls obesity-associated vascular inflammation, oxidative stress and endothelial dysfunction in mice and potentially humans. Thus, CD40L represents a therapeutic target in lipid metabolic disorders which is a leading cause in cardiovascular disease.

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The lifespan determinant p66shc drives obesity-induced oxidative stress, mitochondrial dysfunction and vascular inflammation

European Heart Journal ◽

10.1093/eurheartj/eht308.781 ◽

2013 ◽

Vol 34 (suppl 1) ◽

pp. 781-781 ◽

Cited By ~ 1

Author(s):

F. Paneni ◽

G. Capretti ◽

S. Costantino ◽

S. Chiandotto ◽

A. Akhmedov ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Vascular Inflammation

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Trivalent Chromium Supplementation Inhibits Oxidative Stress, Protein Glycosylation, and Vascular Inflammation in High Glucose-Exposed Human Erythrocytes and Monocytes

Oxidative Stress and Disease - Oxidative Stress and Inflammatory Mechanisms in Obesity, Diabetes, and the Metabolic Syndrome ◽

10.1201/9781420043792.ch20 ◽

2007 ◽

pp. 301-313

Author(s):

Sushil Jain

Keyword(s):

Oxidative Stress ◽

High Glucose ◽

Vascular Inflammation ◽

Stress Protein ◽

Trivalent Chromium ◽

Human Erythrocytes ◽

Protein Glycosylation

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Fine particulate matter (PM2.5) inhalation-induced alterations in the plasma lipidome as promoters of vascular inflammation and insulin resistance

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00881.2020 ◽

2021 ◽

Author(s):

Bradford G. Hill ◽

Benjamin Rood ◽

Amanda Ribble ◽

Petra Haberzettl

Keyword(s):

Oxidative Stress ◽

Fatty Acids ◽

Air Pollution ◽

Vascular Inflammation ◽

Fine Particulate Matter ◽

Cvd Risk ◽

Vegf Signaling ◽

Fine Particulate ◽

Air Pollution Exposure ◽

Pollution Exposure

Fine particulate matter (PM2.5) air pollution exposure increases the risk of developing cardiovascular disease (CVD). Although the precise mechanisms by which air pollution exposure increases CVD risk remain uncertain, research indicates that PM2.5-induced endothelial dysfunction contributes to the CVD risk. Previous studies demonstrate that concentrated PM2.5 (CAP) exposure induces vascular inflammation and impairs insulin and VEGF signaling dependent upon pulmonary oxidative stress. To assess whether CAP exposure induces these vascular effects via plasmatic factors, we incubated aortas from naïve mice with plasma isolated from mice exposed to HEPA-filtered air or CAP (9 d) and examined vascular inflammation and insulin and VEGF signaling. We found that treatment of naïve aortas with plasma from CAP-exposed mice activates NF-κBα and induces insulin and VEGF resistance, indicating transmission by plasmatic factor(s). To identify putative factors, we exposed lung-specific ecSOD-transgenic (ecSOD-Tg) mice and wildtype (WT) littermates to CAP at concentrations of either ~60 µg/m3 (CAP60) or ~100 µg/m3 (CAP100) and measured the abundance of plasma metabolites by mass spectrometry. In WT mice, both CAP concentrations increased levels of fatty acids such as palmitate, myristate, and palmitoleate and decreased numerous phospholipid species; however, these CAP-induced changes in the plasma lipidome were prevented in ecSOD-Tg mice. Consistent with the literature, we found that fatty acids such as palmitate are sufficient to promote endothelial inflammation. Collectively, our findings suggest that PM2.5 exposure, by inducing pulmonary oxidative stress, promotes unique lipidomic changes characterized by high levels of circulating fatty acids, which are sufficient to trigger vascular pathology.

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Role of Cox-2 in Vascular Inflammation: An Experimental Model of Metabolic Syndrome

Mediators of Inflammation ◽

10.1155/2013/513251 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Nicolás F. Renna ◽

Emiliano R. Diez ◽

Carina Lembo ◽

Roberto M. Miatello

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Drinking Water ◽

Experimental Model ◽

Vascular Remodeling ◽

Vascular Inflammation ◽

Left Ventricular ◽

Wky Rats ◽

Cox 2

The objective of this work was to demonstrate the role of COX-2 enzyme at the vascular in experimental model of metabolic syndrome. SHR male WKY rats were employed; they were distributed in 8 groups (n=8each): control (W); W + L: WKY rats receiving 20 mg/kg of lumiracoxib by intraesophageal administration; SHR; SHR + L: SHR + 20 mg/kg of lumiracoxib by intraesophageal administration; Fructose-Fed Rats (FFR): WKY rats receiving 10% (w/v) fructose solution in drinking water during all 12 weeks; FFR + L: FFR + 20 mg/kg of lumiracoxib by intraesophageal administration; Fructose-Fed Hypertensive Rats (FFHR): SHR receiving 10% (w/v) fructose solution in drinking water during all 12 weeks; and FFHR + L: FFHR + 20 mg/kg of lumiracoxib by intraesophageal administration. Metabolic variables, blood pressure, morphometric variables, and oxidative stress variables were evaluated; also MMP-2 and MMP-9 (collagenases), VCAM-1, and NF-κB by Westernblot or IFI were evaluated. FFHR presented all variables of metabolic syndrome; there was also an increase in oxidative stress variables; vascular remodeling and left ventricular hypertrophy were evidenced along with a significant increase in the expression of the mentioned proinflammatory molecules and increased activity and expression of collagenase. Lumiracoxib was able to reverse vascular remodeling changes and inflammation, demonstrating the involvement of COX-2 in the pathophysiology of vascular remodeling in this experimental model.

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Influence of Melatonin on Cerebrovascular Proinflammatory Mediators Expression and Oxidative Stress Following Subarachnoid Hemorrhage in Rabbits

Mediators of Inflammation ◽

10.1155/2009/426346 ◽

2009 ◽

Vol 2009 ◽

pp. 1-6 ◽

Cited By ~ 30

Author(s):

Qi Fang ◽

Gang Chen ◽

Weiwei Zhu ◽

Wanli Dong ◽

Zhong Wang

Keyword(s):

Oxidative Stress ◽

Vascular Inflammation ◽

Autologous Blood ◽

Vehicle Group ◽

Control Group ◽

Proinflammatory Mediators ◽

Melatonin Administration ◽

Basilar Arteries ◽

And Oxidative Stress ◽

Pro Inflammatory Cytokines

The aim of this study is to analyze whether melatonin administration influenced the nuclear factor-kappa B (NF-κB) activity, proinflammatory cytokines expression, and oxidative response in the basilar artery after SAH. A total of 48 rabbits were randomly divided into four groups: control group, SAH group, SAH + vehicle group, and SAH + melatonin group. All SAH animals were subjected to injection of autologous blood into cisterna magna twice on day 0 and day 2. The melatonin was administered intraperitoneally at a dose of 5 mg/kg/12 h simultaneously with SAH from day 0 to day 5. The basilar arteries were extracted on day 5 after SAH. As a result, we found that vascular inflammation and oxidative stress were induced in all SAH animals. In animals given melatonin, basilar arterial NF-κB and pro-inflammatory cytokines were decreased in comparison to vehicle-treated animals. Measures of oxidative stress also showed significant downregulation after melatonin treatment. Furthermore, administration of melatonin prevented vasospasm on day 5 following SAH. In conclusion, post-SAH melatonin administration may attenuate inflammatory response and oxidative stress in the spasmodic artery, and this may be one mechanism involved in the therapeutic effect of melatonin on the subsequent vasospasm after SAH.

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Impact of Exercise and Metabolic Disorders on Heat Shock Proteins and Vascular Inflammation

Autoimmune Diseases ◽

10.1155/2012/836519 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 9

Author(s):

Earl G. Noble ◽

Garry X. Shen

Keyword(s):

Oxidative Stress ◽

Heat Shock ◽

Heat Shock Proteins ◽

Inflammatory Mediators ◽

Metabolic Disorders ◽

Cell Injury ◽

Vascular Inflammation ◽

Atherosclerotic Cardiovascular Disease ◽

Heat Shock Factor 1 ◽

Shock Proteins

Heat shock proteins (Hsp) play critical roles in the body’s self-defense under a variety of stresses, including heat shock, oxidative stress, radiation, and wounds, through the regulation of folding and functions of relevant cellular proteins. Exercise increases the levels of Hsp through elevated temperature, hormones, calcium fluxes, reactive oxygen species (ROS), or mechanical deformation of tissues. Isotonic contractions and endurance- type activities tend to increase Hsp60 and Hsp70. Eccentric muscle contractions lead to phosphorylation and translocation of Hsp25/27. Exercise-induced transient increases of Hsp inhibit the generation of inflammatory mediators and vascular inflammation. Metabolic disorders (hyperglycemia and dyslipidemia) are associated with type 1 diabetes (an autoimmune disease), type 2 diabetes (the common type of diabetes usually associated with obesity), and atherosclerotic cardiovascular disease. Metabolic disorders activate HSF/Hsp pathway, which was associated with oxidative stress, increased generation of inflammatory mediators, vascular inflammation, and cell injury. Knock down of heat shock factor-1 (HSF1) reduced the activation of key inflammatory mediators in vascular cells. Accumulating lines of evidence suggest that the activation of HSF/Hsp induced by exercise or metabolic disorders may play a dual role in inflammation. The benefits of exercise on inflammation and metabolism depend on the type, intensity, and duration of physical activity.

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