Pathogenesis of Myocardial Injury and Cell Death in Myocarditis: Its Relation to the Fas/Fas Ligand Pathway

Heart Failure ◽  
2000 ◽  
pp. 57-69 ◽  
Author(s):  
Michiaki Hiroe ◽  
Tetsuya Toyozaki
Keyword(s):  
Cell Death ◽  
Myocardial Injury ◽  
Fas Ligand

scholarly journals sFasL—The Key to a Riddle: Immune Responses in Aging Lung and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2177
Author(s):  
Shulamit B. Wallach-Dayan ◽  
Dmytro Petukhov ◽  
Ronit Ahdut-HaCohen ◽  
Mark Richter-Dayan ◽  
Raphael Breuer
Keyword(s):  
Cell Death ◽  
Lung Disease ◽  
Fas Ligand ◽  
Death Receptor ◽  
Mesenchymal Cells ◽  
Soluble Form ◽  
Cell Accumulation ◽  
Key Factor ◽  
Aged Subjects

By dint of the aging population and further deepened with the Covid-19 pandemic, lung disease has turned out to be a major cause of worldwide morbidity and mortality. The condition is exacerbated when the immune system further attacks the healthy, rather than the diseased, tissue within the lung. Governed by unremittingly proliferating mesenchymal cells and increased collagen deposition, if inflammation persists, as frequently occurs in aging lungs, the tissue develops tumors and/or turns into scars (fibrosis), with limited regenerative capacity and organ failure. Fas ligand (FasL, a ligand of the Fas cell death receptor) is a key factor in the regulation of these processes. FasL is primarily found in two forms: full length (membrane, or mFasL) and cleaved (soluble, or sFasL). We and others found that T-cells expressing the mFasL retain autoimmune surveillance that controls mesenchymal, as well as tumor cell accumulation following an inflammatory response. However, mesenchymal cells from fibrotic lungs, tumor cells, or cells from immune-privileged sites, resist FasL+ T-cell-induced cell death. The mechanisms involved are a counterattack of immune cells by FasL, by releasing a soluble form of FasL that competes with the membrane version, and inhibits their cell death, promoting cell survival. This review focuses on understanding the previously unrecognized role of FasL, and in particular its soluble form, sFasL, in the serum of aged subjects, and its association with the evolution of lung disease, paving the way to new methods of diagnosis and treatment.

Dephosphorylation of Fas-ligand and caveolin-1 is a prerequisite step in Fas-ligand - caveolin-1 complex formation and cell death stimulation

2020 ◽  
Vol 70 ◽  
pp. 109590
Author(s):  
Xenia A. Glukhova ◽  
Julia A. Trizna ◽  
Olga V. Proussakova ◽  
Vladimir G. Gogvadze ◽  
Igor P. Beletsky
Keyword(s):  
Cell Death ◽  
Complex Formation ◽  
Fas Ligand ◽  
Caveolin 1

The Fas ligand as a cell death factor and signal transducer

2003 ◽  
Vol 3 (12) ◽  
pp. 33-46 ◽  
Author(s):  
Andreas Linkermann ◽  
Jing Qian ◽  
Dieter Kabelitz ◽  
Ottmar Janssen
Keyword(s):  
Cell Death ◽  
Fas Ligand ◽  
Signal Transducer ◽  
A Cell

Abstract 060: CCN1/a 6 β 1 Mediates Myocardial Injuries Induced by Work Overload or by Doxorubicin in Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Pei-Ling I Hsu ◽  
Fan-E Mo
Keyword(s):  
Myocardial Injury ◽  
Fas Ligand ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Myocardial Damage ◽  
Matricellular Protein ◽  
Work Overload ◽  
Myocardial Injuries ◽  
Injury Models

Introduction: Matricellular protein CCN1 is expressed in myocardial infarction, pressure overload, and ischemia in mice, and in patients with a failing heart. Despite its well-documented angiogenic activities, CCN1 promotes fibroblast apoptosis in some contexts. The role of CCN1 in an injured heart was not clear. We assessed the hypothesis that CCN1 plays a detrimental role and mediates cardiac injury through its proapoptotic activities. Methods and Results: To test the role of CCN1 in cardiac injury, we employed two different myocardial injury models in mice, including a work-overload-induced injury created by isoproterenol treatment (ISO; 100 mg/kg/day; s.c. for 5 days; n= 6 for each group) and an injury induced by the cardiotoxicity of doxorubicin (DOX, single dose of 15 mg/kg; i.p. sacrificed after 14 days). Ccn1 expression was induced in the damaged myocardium in both injury models. A line of knock-in mice carrying an apoptosis-defective Ccn1 mutant allele, Ccn1-dm , which has disrupted integrin α 6 β 1 binding sites, were tested in the ISO- or DOX -induced cardiac injury. Myocardial damage was seen in tissues from wile-type (WT) hearts after receiving ISO. Ccn1 dm/dm (DM) mice possessed remarkable resistance against ISO or DOX treatments and exhibited no tissue damage or fibrosis compared to WT mice after H&E or Masson’s trichrome stainings. DM mice were resistant to both ISO- and DOX-induced cardiac cell apoptosis, indicating that CCN1 is critically mediating cardiomyocyte apoptotic death in cardiac injury. Moreover, we found that death factor Fas ligand (FasL) and its receptor Fas were upregulated in WT mice receiving ISO or DOX treatments by immunohistochemical staining, compared with the PBS-control. 8-OHdG-positive, a marker for oxidative stress, cardiomyocytes were increased by ISO or DOX treatments as well. In contrast, the expression of Fas/FasL, and the 8-OHdG-positive cardiomyocytes in the myocardium of DM mice were not changed by ISO or DOX. Conclusions: We identify CCN1 as a novel pathophysiological regulator of cardiomyocyte apoptosis in cardiac injury. Blocking apoptotic function of CCN1 effectively prevents myocardial injury in mice. CCN1 and its receptor α 6 β 1 represent promising future therapeutic targets in cardiac injury.

scholarly journals Fas ligand mediates activation-induced cell death in human T lymphocytes.

1995 ◽  
Vol 181 (1) ◽  
pp. 71-77 ◽  
Author(s):  
M R Alderson ◽  
T W Tough ◽  
T Davis-Smith ◽  
S Braddy ◽  
B Falk ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Fas Ligand ◽  
Significant Proportion ◽  
Cell Receptor ◽  
Target Cells ◽  
Activated T Cells ◽  
Activation Induced Cell Death ◽  
Fas L

A significant proportion of previously activated human T cells undergo apoptosis when triggered through the CD3/T cell receptor complex, a process termed activation-induced cell death (AICD). Ligation of Fas on activated T cells by either Fas antibodies or recombinant human Fas-ligand (Fas-L) also results in cytolysis. We demonstrate that these two pathways of apoptosis are causally related. Stimulation of previously activated T cells resulted in the expression of Fas-L mRNA and lysis of Fas-positive target cells. Fas-L antagonists inhibited AICD of T cell clones and staphylococcus enterotoxin B (SEB)-specific T cell lines. The data indicate AICD in previously stimulated T cells is mediated by Fas/Fas-L interactions.

scholarly journals Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Mari Kamiya ◽  
Fumitaka Mizoguchi ◽  
Kimito Kawahata ◽  
Dengli Wang ◽  
Masahiro Nishibori ◽  
...  
Keyword(s):  
Cell Death ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Muscle Cell ◽  
Muscle Injury ◽  
Fas Ligand ◽  
Muscle Fibers ◽  
Inflammatory Molecules

AbstractMuscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.

Abstract 2422: Short Term Effects of Milrinone on Biomarkers in Severe Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
David Lanfear ◽  
Ramesh C Gupta ◽  
Rasha N Bazari ◽  
Reema Hasan ◽  
Celeste Williams ◽  
...  
Keyword(s):  
Heart Failure ◽  
Myocardial Injury ◽  
Fas Ligand ◽  
Troponin I ◽  
Severe Heart Failure ◽  
Myocardial Necrosis ◽  
Adverse Outcomes ◽  
P Values ◽  
Damage Initiation ◽  
Tnf Α

Introduction: Inotrope use is associated with adverse outcomes in heart failure (HF), raising concern that it may cause or accelerate myocardial injury/damage. Whether biomarkers of myocardial necrosis, stretch, inflammation and apoptosis change in response to inotrope initiation is not known. Methods: Ten patients with severe HF and cardiac index < 2.0 L/m/M2 who were planned to receive intravenous milrinone were studied. All patients were at bed rest in cardiac intensive care unit. Blood was drawn immediately before initiation of milrinone and after 24 hours of continuous infusion. Milrinone dosing was at the discretion of the patient’s attending physician (0.375 –0.5 mcg/kg/min were used). Blood samples were immediately centrifuged, plasma aliquoted, and frozen at -70°C. Troponin I (TnI), Myoglobin, N-terminal pro-BNP (NTproBNP), interleukin 6 (IL6), Tumor Necrosis Factor α (TNF α), soluble Fas (sFas), and Fas ligand (FasL) levels were measured. TnI levels were replicated to assess precision of measurement, yielding a correlation coefficient > 0.995 and power > 90% to detect a mean difference as small as 0.02 ng/ml. Statistical comparisons were made between baseline levels and 24 hour levels using the paired t-test. P values < 0.05 were considered significant. Results: Baseline mean biomarker levels, 24 hour levels, absolute change, percent change, and associated p-values are shown in the Table . Troponin I was elevated at baseline in all patients (range 0.0205– 0.56 ng/ml). There was no significant change in TnI after 24 hours of milrinone compared to baseline. There were significant improvements in NTproBNP, IL6, TNF α, sFas, and FasL. Conclusions: In this sample of patients with severe HF and reduced cardiac output, all had elevated troponin at baseline, consistent with ongoing myocardial damage. Initiation of milrinone therapy did not result in changes indicative of accelerated myocardial injury, and was associated with salutary effects on other markers. This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin). Change in Biomarker Levels at 24 hours of Milrinone Therapy

Biochemical Characterisation of an In Vitro Model of Hepatocellular Apoptotic Cell Death

2009 ◽  
Vol 37 (2) ◽  
pp. 209-218 ◽  
Author(s):  
Mathieu Vinken ◽  
Elke Decrock ◽  
Elke De Vuyst ◽  
Luc Leybaert ◽  
Tamara Vanhaecke ◽  
...  
Keyword(s):  
Cell Death ◽  
In Vitro Model ◽  
Caspase 3 ◽  
Fas Ligand ◽  
Apoptotic Cell ◽  
Annexin V ◽  
Apoptotic Cell Death ◽  
Biochemical Characterisation ◽  
Vitro Model

This study was set up to critically evaluate a commonly-used in vitro model of hepatocellular apoptotic cell death, in which freshly isolated hepatocytes, cultured in a monolayer configuration, are exposed to a combination of Fas ligand and cycloheximide for six hours. A set of well-acknowledged cell death markers was addressed: a) cell morphology was studied by light microscopy; b) apoptotic and necrotic cell populations were quantified by in situ staining with Annexin-V, Hoechst 33342 and propidium iodide (PI); c) apoptotic and necrotic activities were monitored by probing caspase 3-like activity and measuring the extracellular leakage of lactate dehydrogenase (LDH), respectively; and d) the expression of apoptosis regulators was investigated by immunoblotting. The initiation of apoptosis was evidenced by the activation of caspase 8 and caspase 9, and increased Annexin-V reactivity. Progression through the apoptotic process was confirmed by the activation of caspase 3 and Bid, the enhanced expression of Bax, and the occurrence of nuclear fragmentation. Late transition to a necrotic appearance was demonstrated by an increased number of PI-positive cells and augmented extracellular release of LDH. Thus, the in vitro model allows the study of the entire course of Fas-mediated hepatocellular apoptotic cell death, which is not possible in vivo. This experimental system can serve a broad range of in vitro pharmaco-toxicological purposes, thereby directly assisting in the reduction of animal experimentation.

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