P717Glucagon-like peptide 1 (GLP-1) improves endothelial dysfunction and vascular inflammation in polymicrobial sepsis induced by cecal ligation and puncture (CLP)

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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Short-term Effects of Metformin on Cardiac and Peripheral Blood Cells Following Cecal Ligation and Puncture-induced Sepsis

Drug Research ◽

10.1055/a-1322-7478 ◽

2020 ◽

Author(s):

Tina Didari ◽

Shokoufeh Hassani ◽

Maryam Baeeri ◽

Mona Navaei-Nigjeh ◽

Mahban Rahimifard ◽

...

Keyword(s):

Oxidative Stress ◽

Weight Loss ◽

Blood Cells ◽

Cell Injury ◽

Antioxidant Properties ◽

Cecal Ligation ◽

Neutrophil Infiltration ◽

Cardiac Cells ◽

Cecal Ligation And Puncture ◽

Blood Profile

Abstract Aim of the study Sepsis has well-documented inflammatory effects on cardiovascular and blood cells. This study is designed to investigate potential anti-inflammatory effects of metformin on cardiac and blood cells 12 and 24 h following cecal ligation and puncture (CLP)-induced sepsis. Methods For the purpose of this study, 36 male Wistar rats were divided into six groups: two groups underwent CLP, two groups underwent CLP and received metformin, and two groups only received sham operations. 12 h later, 18 rats (half of rats in each of the three aforementioned groups) were sacrificed and cardiac and blood cells were harvested. Subsequently, 12 h later, the rest of the rats were euthanatized. In all harvested blood and cardiac cells, oxidative stress indicators, antioxidant properties, count of blood cells, neutrophil infiltration, percentage of weight loss and pathological assessment were conducted. Results In our experiment, metformin elevated antioxidant levels, improved function of blood cells and percentage of weight loss. Moreover, in the groups which received metformin, oxidative stress and neutrophil infiltration markers were decreased significantly. Moreover, pathological investigations of cardiac cell injury were reduced in the metformin group. Conclusions Our findings suggest that in CLP induced sepsis model, metformin can improve the function of blood and cardiac cells through alleviating inflammation, improvement of anti-inflammation properties, and enhancement of blood profile, and all these effects are more pronounced after 24 h in comparison with 12 h after induction of sepsis.

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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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Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

Experimental Diabetes Research ◽

10.1155/2012/481840 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 56

Author(s):

Basma Basha ◽

Samson Mathews Samuel ◽

Chris R. Triggle ◽

Hong Ding

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Clinical Trials ◽

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Cardiovascular Complications ◽

Therapeutic Agents ◽

Recent Past

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

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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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A COX-2/sEH dual inhibitor PTUPB ameliorates cecal ligation and puncture-induced sepsis in mice via anti-inflammation and anti-oxidative stress

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.109907 ◽

2020 ◽

Vol 126 ◽

pp. 109907 ◽

Cited By ~ 8

Author(s):

Yan-Feng Zhang ◽

Chen-Chen Sun ◽

Jia-Xi Duan ◽

Hui-Hui Yang ◽

Chen-Yu Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Cecal Ligation ◽

Cecal Ligation And Puncture ◽

Dual Inhibitor ◽

Cox 2 ◽

Anti Inflammation

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The cordycepin derivative IMM-H007 improves endothelial dysfunction by suppressing vascular inflammation and promoting AMPK-dependent eNOS activation in high-fat diet-fed ApoE knockout mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2019.02.045 ◽

2019 ◽

Vol 852 ◽

pp. 167-178 ◽

Cited By ~ 2

Author(s):

Min-jie Wang ◽

Xue-ying Peng ◽

Ze-qin Lian ◽

Hai-bo Zhu

Keyword(s):

Endothelial Dysfunction ◽

Knockout Mice ◽

High Fat Diet ◽

Vascular Inflammation ◽

High Fat ◽

Apoe Knockout Mice

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Differential effect of imipenem treatment on injury caused by cecal ligation and puncture in wild-type and NK cell-deficient β2-microgloblin knockout mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00338.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. G277-G284 ◽

Cited By ~ 6

Author(s):

Victor T. Enoh ◽

Cheng Y. Lin ◽

Tushar K. Varma ◽

Edward R. Sherwood

Keyword(s):

Metabolic Acidosis ◽

Knockout Mice ◽

Nk Cell ◽

Plasma Concentrations ◽

Cecal Ligation ◽

Systemic Infection ◽

Cecal Ligation And Puncture ◽

Wild Type ◽

Term Survival ◽

The Impact

Our previous studies showed that β2-microglobulin knockout mice treated with anti-asialoGM1 (β2MKO/αAsGM1 mice) are resistant to injury caused by cecal ligation and puncture (CLP). However, CLP-induced injury is complex. Potential mechanisms of injury include systemic infection, cecal ischemia, and translocation of bacterial toxins such as endotoxin and superantigens. Currently, it is unclear which of these mechanisms of injury contributes to mortality in wild-type mice and whether β2MKO/αAsGM1 mice are resistant to any particular mechanisms of injury. In the present study, we hypothesized that systemic infection is the major cause of injury after CLP in wild-type mice and that β2MKO/αAsGM1 mice are resistant to infection-induced injury. To test this hypothesis, wild-type and β2MKO/αAsGM1 mice were treated with the broad-spectrum antibiotic imipenem immediately after CLP to decrease the impact of systemic infection in our model. Treatment of wild-type and β2MKO/αAsGM1 mice with imipenem decreased bacterial counts by at least two orders of magnitude. However, all wild-type mice, whether treated with saline or imipenem, died by 42 h after CLP and had significant hypothermia, metabolic acidosis, and high plasma concentrations of the cytokines interleukin-6, macrophage inflammatory protein-2, and keratinocyte-derived chemokine. β2MKO/αAsGM1 mice showed 40% long-term survival, which was increased to 90% by imipenem treatment. β2MKO/αAsGM1 mice had less hypothermia, decreased metabolic acidosis, and lower cytokine concentrations at 18 h after CLP compared with wild-type mice. These results suggest that infection is not the major cause of mortality for wild-type mice in our model of CLP. Other mechanisms of injury such as cecal ischemia or translocation of microbial toxins may be more important. β2MKO/αAsGM1 mice appear resistant to these early, non-infection-related causes of CLP-induced injury but showed delayed mortality associated with bacterial dissemination, which was ablated by treatment with imipenem.

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Transient Receptor Potential Melastatin 2 Protects Mice against Polymicrobial Sepsis by Enhancing Bacterial Clearance

Anesthesiology ◽

10.1097/aln.0000000000000275 ◽

2014 ◽

Vol 121 (2) ◽

pp. 336-351 ◽

Cited By ~ 30

Author(s):

XiaoWei Qian ◽

Tomohiro Numata ◽

Kai Zhang ◽

CaiXia Li ◽

JinChao Hou ◽

...

Keyword(s):

Bone Marrow ◽

Knockout Mice ◽

Transient Receptor Potential ◽

Cecal Ligation ◽

Polymicrobial Sepsis ◽

Bacterial Clearance ◽

Cecal Ligation And Puncture ◽

Bacterial Burden ◽

Wild Type ◽

Transient Receptor Potential Melastatin

Abstract Background: Recent studies suggest that the transient receptor potential melastatin 2 (TRPM2) channel plays an important role in inflammation and immune response. However, the role and mechanism of TRPM2 in polymicrobial sepsis remain unclear. Methods: The authors explored the effects of genetic disruption of TRPM2 on mortality (n = 15), bacterial clearance (n = 6), organ injury, and systemic inflammation during cecal ligation and puncture–induced sepsis. Electrophysiology, immunoblot, bacterial clearance experiment, and quantitative real-time polymerase chain reaction were used to explore the role and mechanism of TRPM2 in sepsis. Results: After cecal ligation and puncture, Trpm2-knockout mice had increased mortality compared with wild-type mice (73.3 vs. 40%, P = 0.0289). The increased mortality was associated with increased bacterial burden, organ injury, and systemic inflammation. TRPM2-mediated Ca2+ influx plays an important role in lipopolysaccharide or cecal ligation and puncture–induced heme oxygenase-1 (HO-1) expression in macrophage. HO-1 up-regulation decreased bacterial burden both in wild-type bone marrow–derived macrophages and in cecal ligation and puncture–induced septic wild-type mice. Disruption of TRPM2 decreased HO-1 expression and increased bacterial burden in bone marrow–derived macrophages. Pretreatment of Trpm2-knockout bone marrow–derived macrophages with HO-1 inducer markedly increased HO-1 expression and decreased bacterial burden. Pretreatment of Trpm2-knockout mice with HO-1 inducer reversed the susceptibility of Trpm2-knockout mice to sepsis by enhancing the bacterial clearance. In addition, septic patients with lower monocytic TRPM2 and HO-1 messenger RNA levels had a worse outcome compared with septic patients with normal monocytic TRPM2 and HO-1 messenger RNA levels. TRPM2 levels correlated with HO-1 levels in septic patients (r = 0.675, P = 0.001). Conclusion: The study data demonstrate a protective role of TRPM2 in controlling bacterial clearance during polymicrobial sepsis possibly by regulating HO-1 expression.

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