The Synthetic Pentasaccharide, Fondaparinux, Reduces Inflammation and Neutrophil Accumulation in Kidney Ischemia-Reperfusion Injury.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 217-217 ◽  
Author(s):  
Gernot Schabbauer ◽  
Rolf D. Frank ◽  
Todd Holscher ◽  
Yuichiro Sato ◽  
Michael Tencati ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Inflammatory Diseases ◽  
Anticoagulant Activity ◽  
Ischemia Reperfusion ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Inflammatory Cells ◽  
Neutrophil Accumulation ◽  
Kidney Ischemia

Abstract Acute inflammatory diseases are often accompanied by coagulation activation leading to local thrombotic complications and disseminated intravascular coagulation. Recent studies support the concept of crosstalk between coagulation and inflammation. The synthetic pentasaccharide, fondaparinux, is a selective antithrombin-dependent inhibitor of coagulation factor Xa. In this study, we investigated the effect of fondaparinux in a lethal murine model of kidney ischemia-reperfusion (I/R) injury that is associated with coagulation and inflammation. Fondaparinux treatment of I/R-injured mice significantly reduced serum creatinine levels and increased survival from 0 to 44% compared with saline treated control mice. In contrast, depletion of fibrinogen with ancrod was not protective, suggesting that fondaparinux may have additional properties beyond its anticoagulant activity. Indeed, fondaparinux significantly reduced IL-6 and MIP-2 expression but did not reduce MCP-1 expression. Furthermore, fondaparinux significantly decreased neutrophil accumulation in the injured kidneys. Finally, we showed that fondaparinux reduced recruitment of neutrophils into the peritoneum in a model of acute peritonitis and inhibited the binding of U937 cells to P-selectin in vitro. Our data indicate that fondaparinux has both anticoagulant and anti-inflammatory activity reducing fibrin deposition and blocking the binding of inflammatory cells to activated endothelium. Fondaparinux may be useful in the treatment of acute inflammatory diseases.

A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury

2006 ◽  
Vol 96 (12) ◽  
pp. 802-806 ◽  
Author(s):  
Rolf Frank ◽  
Todd Holscher ◽  
Gernot Schabbauer ◽  
Michael Tencati ◽  
Rafal Pawlinski ◽  
...  
Keyword(s):  
Murine Model ◽  
Ischemia Reperfusion Injury ◽  
Anticoagulant Activity ◽  
Ischemia Reperfusion ◽  
Factor Xa ◽  
U937 Cells ◽  
Chemically Modified ◽  
Prevention And Treatment ◽  
Anti Inflammatory

SummaryFondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in an antithrombin-dependent fashion.This newly developed anticoagulant is used in the prevention and treatment of venous thromboembolism. Recently, we showed that fondaparinux reduces inflammation and protects the kidney from ischemia-reperfusion (I/R) injury. However, the relative contributions of the anticoagulant and anti-inflammatory activities of fondaparinux to the observed protection is unknown.To address this, we chemically modified fondaparinux to abolish its affinity for antithrombin and analyzed the effect of this non-anti- coagulant (NAC)-pentasaccharide on binding of U937 cells to P-selectin in vitro and on inflammation in a murine model of kidney I/R injury. NAC-pentasaccharide was as effective as fondaparinux at inhibiting the binding of U937 cells to P-selectin.In addition, NAC-pentasaccharide significantly reduced IL-6 and MIP-2 expression and injury in the kidney I/R model.These findings indicate that the anti-inflammatory activity of fondaparinux can be dissociated from its anticoagulant activity and that NACpentasaccharide is protective in kidney I/R injury.

scholarly journals Enhancer of zeste homolog 2 modulates oxidative stress‐mediated pyroptosis in vitro and in a mouse kidney ischemia‐reperfusion injury model

2019 ◽  
Vol 34 (1) ◽  
pp. 835-852 ◽  
Author(s):  
Hao Liu ◽  
Zhiyuan Chen ◽  
Xiaodong Weng ◽  
Hui Chen ◽  
Yang Du ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mouse Kidney ◽  
Injury Model ◽  
Enhancer Of Zeste ◽  
Kidney Ischemia

scholarly journals Inhibition of BRD4 Reduces Neutrophil Activation and Adhesion to the Vascular Endothelium Following Ischemia Reperfusion Injury

2020 ◽  
Vol 21 (24) ◽  
pp. 9620
Author(s):  
Shelby Reid ◽  
Noah Fine ◽  
Vikrant K. Bhosle ◽  
Joyce Zhou ◽  
Rohan John ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Adhesion ◽  
Neutrophil Accumulation ◽  
Iri Model ◽  
Brd4 Inhibition

Renal ischemia reperfusion injury (IRI) is associated with inflammation, including neutrophil infiltration that exacerbates the initial ischemic insult. The molecular pathways involved are poorly characterized and there is currently no treatment. We performed an in silico analysis demonstrating changes in NFκB-mediated gene expression in early renal IRI. We then evaluated NFκB-blockade with a BRD4 inhibitor on neutrophil adhesion to endothelial cells in vitro, and tested BRD4 inhibition in an in vivo IRI model. BRD4 inhibition attenuated neutrophil adhesion to activated endothelial cells. In vivo, IRI led to increased expression of cytokines and adhesion molecules at 6 h post-IRI with sustained up-regulated expression to 48 h post-IRI. These effects were attenuated, in part, with BRD4 inhibition. Absolute neutrophil counts increased significantly in the bone marrow, blood, and kidney 24 h post-IRI. Activated neutrophils increased in the blood and kidney at 6 h post-IRI and remained elevated in the kidney until 48 h post-IRI. BRD4 inhibition reduced both total and activated neutrophil counts in the kidney. IRI-induced tubular injury correlated with neutrophil accumulation and was reduced by BRD4 inhibition. In summary, BRD4 inhibition has important systemic and renal effects on neutrophils, and these effects are associated with reduced renal injury.

In Vitro Evaluation of Apixaban, a Novel, Potent, Selective and Orally Bioavailable Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4130-4130 ◽  
Author(s):  
Joseph M. Luettgen ◽  
Tracy A. Bozarth ◽  
Jeffrey M. Bozarth ◽  
Frank A. Barbera ◽  
Patrick Y. Lam ◽  
...  
Keyword(s):  
Human Plasma ◽  
Serine Proteases ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Competitive Inhibitor ◽  
Rat Plasma ◽  
Reversible Inhibitor ◽  
Antithrombotic Agent

Abstract Apixaban, previously known as BMS-562247, is a high affinity, highly selective, orally-active, reversible inhibitor of coagulation factor Xa (fXa), in clinical studies as a therapeutic agent for prevention and treatment of thromboembolic diseases. The in vitro characteristics of apixaban were evaluated in purified systems and in human blood from healthy volunteers. Detailed kinetic analysis of apixaban inhibition of human fXa showed that it is a readily reversible, potent and competitive inhibitor versus a synthetic tripeptide substrate with a Ki of 0.08 nM, an association rate of 2 × 107 M−1s−1and a dissociation half life of 3.4 min. Weak affinity (Ki ~3 μM) is observed for thrombin, plasma kallikrein, and chymotrypsin. Affinity for trypsin and all other serine proteases tested is negligible with Ki > 15 μM. Apixaban is an effective inhibitor of free fXa and of prothrombinase, in buffer, platelet poor plasma, and whole blood. The anticoagulant activity of apixaban was determined in platelet-poor human plasma. Apixaban causes concentration dependent prolongation of the fXa mediated clotting assays. The human plasma concentration required to produce a doubling of the clotting time is 3.6 μM for prothrombin time, 7.4 μM for activated partial thromboplastin time and 0.4 μM for HepTest. To support preclinical efficacy and safety studies purified fXa from rabbit, dog and rat plasma was also found to be inhibited by apixaban (0.17, 2.6, and 1.3 nM, respectively). In summary the in vitro properties of apixaban show that it is a highly selective and potentially potent antithrombotic agent for venous and arterial thrombotic diseases.

scholarly journals P1750Inhibition of coagulation factor xa attenuates myocardial ischemia reperfusion injury in mice

2017 ◽  
Vol 38 (suppl_1) ◽  
Author(s):  
J.J.N. Posma ◽  
J.J. Posthuma ◽  
R. Van Oerle ◽  
S. Heitmeier ◽  
H. Ten Cate ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

scholarly journals Resolvin D1 inhibits endothelial permeability and mitochondrial damage following cardiac ischemia reperfusion in diabetic mice

2021 ◽  
Author(s):  
Jialiang Zhang ◽  
Fangyang Huang ◽  
Li Chen ◽  
Guoyong Li ◽  
Dan Xiao ◽  
...  
Keyword(s):  
Infarct Size ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Endothelial Permeability ◽  
Mitochondrial Damage ◽  
Diabetic Mice ◽  
Resolvin D1

Abstract Purpose Novel strategies for preventing myocardial ischemia reperfusion injury (MIRI) in a diabetic heart are urgently needed. Resolvin D1 (RvD1) plays important therapeutic roles in inflammatory diseases. However, the therapeutic role of RvD1 in diabetic MIRI is still unknown. Methods Diabetic mice were established with a high-fat diet and streptozotocin (STZ). The mice were pretreated with RvD1 via intraperitoneal injection for 3 days, followed by MIRI. To evaluate the effects of RvD1 on chronic cardiac remodelling, RvD1 was administered for another 2 weeks after MIRI. The effects of RvD1 following MIRI were measured, including the severity of infarct size, regional inflammation, cardiac function, and permeability of cultured endothelial monolayers. Mitochondrial reactive oxygen species (MitoROS) and mitochondrial membrane potential (MMP) were determined using MitoSOX and JC-1. Results RvD1 pretreatment significantly reduced infarct size and the Evans blue content in diabetic injured hearts, which was associated with improved endothelial permeability. At 2 weeks after MIRI, RvD1 treatment partially improved cardiac performance and reduced cardiac fibrosis in diabetic MIRI mice. In vitro, RvD1 attenuated endothelial leakage induced by hypoxia-reoxygenation, H2O2, and lipopolysaccharide (LPS) under high glucose (HG) conditions. Meanwhile, RvD1 remarkably protected endothelial cells from H2O2-induced mitochondrial damage, as evidenced by increased MMP and decreased MitoROS, which was associated with the preservation of VE-cadherin. Conclusion RvD1 alleviates MIRI-induced endothelial permeability and mitochondrial damage injuries in diabetic hearts. Therefore, RvD1 could be a potential therapeutic target for MIRI in diabetes.

scholarly journals Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1889 ◽  
Author(s):  
Nadezhda Novichikhina ◽  
Ivan Ilin ◽  
Anna Tashchilova ◽  
Alexey Sulimov ◽  
Danil Kutov ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Protein Targets ◽  
Ic50 Value ◽  
Anticoagulant Drugs ◽  
Factor Xia ◽  
Derivatives Of

Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1-ij]quinolin-2(1H)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-ij]quinolin-2(1H)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C6,8,9 positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC50 value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor.

MicroRNA-141 regulates the expression level of ICAM-1 on endothelium to decrease myocardial ischemia-reperfusion injury

2015 ◽  
Vol 309 (8) ◽  
pp. H1303-H1313 ◽  
Author(s):  
Rong Rong Liu ◽  
Jun Li ◽  
Jiu Yu Gong ◽  
Fang Kuang ◽  
Jia Yun Liu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Expression Level ◽  
Novel Target ◽  
Myocardial Ischemia Reperfusion

A growing number of studies have suggested microRNAs (miRNAs) are involved in the modulation of myocardial ischemia-reperfusion (MI/R) injury; however, the role of endogenous miRNAs targeting endothelial cells (ECs) and its interaction with ICAM-1 in the setting of MI/R remain poorly understood. Our microarray results showed that miR-146a, miR-146b-5p, miR-155*, miR-155, miR-497, and miR-451 were significantly upregulated, whereas, miR-141 and miR-564 were significantly downregulated in the ECs challenged with TNF-α for 6 h. Real-time PCR analyses additionally validated that the expression levels of miR-146a, miR-155*, and miR-141 were consistent with the microarray results. Then, ICAM-1 was identified as a novel target of miR-141 by Target Scan software and the reporter gene system. Further functional experiments showed that elevated levels of miR-141 inhibited ICAM-1 expression and diminished leukocytes adhesion to ECs in vitro. In an in vivo murine model of MI/R injury, pretreatment with miR-141 mimics through the tail vein downregulated the expression level of ICAM-1 in heart and attenuated MI/R injury as evidenced by decreased infarct size and decline of serum cardial troponin I (cTnI) and lactate dehydrogenase (LDH) concentration. The cardioprotective effects of miR-141 mimics may be attributed to the decreased infiltration of CD11b+ cells and F4/80+ macrophages into ischemic myocardium tissue. In conclusion, our results demonstrate that miR-141, as a novel repressor of ICAM-1, is involved in the attenuation of MI/R injury via antithetical regulation of ICAM-1 and inflammatory cells infiltration. Thus miR-141 may constitute a new therapeutic target in the setting of ischemic heart disease.

scholarly journals NLRP2 is highly expressed and promotes apoptosis in a mouse model of kidney ischemia/reperfusion injury

2019 ◽  
Vol 17 ◽  
pp. 205873921985980 ◽  
Author(s):  
Xueyuan Yu ◽  
Xiumei Zhang ◽  
Zhao Hu
Keyword(s):  
Acute Kidney Injury ◽  
Mouse Model ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Quantitative Polymerase Chain Reaction ◽  
Kidney Injury ◽  
Kidney Ischemia

The aim of this study was to investigate the role of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 2 (NLRP2) in kidney ischemia/reperfusion injury. A mouse model of acute kidney ischemia/reperfusion injury was established to conduct in vivo experiments. Oxygen–glucose deprivation (OGD) and cobalt chloride treatment of the HK-2 and glomerular endothelial cell (GENC) kidney cell lines were performed for the in vitro study. Reverse transcription–quantitative polymerase chain reaction, western blotting, and immunohistochemical staining were used to analyze NLRP2 expression levels. Knockdown of NLRP2 in cells was also performed, and cell apoptosis was detected using flow cytometry. NLRP2 was expressed in normal kidney tissues; however, its expression was significantly increased in the acute kidney injury model and in OGD-treated cells. Conversely, knockdown of NLRP2 reduced apoptosis of cells. These results suggested that NLRP2 was involved in kidney damage and may be an important target for treatment of acute kidney injury.

scholarly journals Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1

2020 ◽  
Vol 31 (3) ◽  
pp. 501-516 ◽  
Author(s):  
Ganeshkumar Rajendran ◽  
Michael P. Schonfeld ◽  
Ratnakar Tiwari ◽  
Shengping Huang ◽  
Rafael Torosyan ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Oxygen Sensor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Inflammatory Cells ◽  
Renal Ischemia ◽  
Renal Ischemia Reperfusion Injury

BackgroundProlyl-4-hydroxylase domain-containing proteins 1–3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined.MethodsTo investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2.ResultsEndothelial deletion of Phd2 preserved kidney function and limited transition to CKD. Mechanistically, we found that endothelial Phd2 ablation protected against renal ischemia-reperfusion injury by suppressing the expression of proinflammatory genes and recruitment of inflammatory cells in a manner that was dependent on HIF-1 but not HIF-2. Persistence of renoprotective responses after acute inducible endothelial-specific loss of Phd2 in adult mice ruled out a requirement for PHD2 signaling in hematopoietic cells. Although Phd2 inhibition was not sufficient to induce detectable HIF activity in the kidney endothelium, in vitro experiments implicated a humoral factor in the anti-inflammatory effects generated by endothelial PHD2/HIF-1 signaling.ConclusionsOur findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.

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