scholarly journals The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Edio Maldonado ◽  
Diego A. Rojas ◽  
Fabiola Urbina ◽  
Aldo Solari
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Heart Failure ◽  
Immune Response ◽  
Chronic Inflammation ◽  
Chagas Disease ◽  
Genetic Factors ◽  
Cardiac Tissue ◽  
Chronic Phase

Chagas disease is a neglected tropical disease caused by the flagellated protozoa Trypanosoma cruzi that affects several million people mainly in Latin American countries. Chagas disease has two phases, which are acute and chronic, both separated by an indeterminate time period in which the infected individual is relatively asymptomatic. The acute phase extends for 40-60 days with atypical and mild symptoms; however, about 30% of the infected patients will develop a symptomatic chronic phase, which is characterized by either cardiac, digestive, neurological, or endocrine problems. Cardiomyopathy is the most important and severe result of Chagas disease, which leads to left ventricular systolic dysfunction, heart failure, and sudden cardiac death. Most deaths are due to heart failure (70%) and sudden death (30%) resulting from cardiomyopathy. During the chronic phase, T. cruzi-infected macrophages respond with the production of proinflammatory cytokines and production of superoxide and nitric oxide by the NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) enzymes, respectively. During the chronic phase, myocardial changes are produced as a result of chronic inflammation, oxidative stress, fibrosis, and cell death. The cellular inflammatory response is mainly the result of activation of the NF-κB-dependent pathway, which activates gene expression of inflammatory cytokines, leading to progressive tissue damage. The persisting production of reactive oxygen species (ROS) is the result of mitochondrial dysfunction in the cardiomyocytes. In this review, we will discuss inflammation and oxidative damage which is produced in the heart during the chronic phase of Chagas disease and recent evidence on the role of macrophages and the production of proinflammatory cytokines during the acute phase and the origin of macrophages/monocytes during the chronic phase of Chagas disease. We will also discuss the contributing factors and mechanisms leading to the chronic inflammation of the cardiac tissue during the chronic phase of the disease as well as the innate and adaptive host immune response. The contribution of genetic factors to the progression of the chronic inflammatory cardiomyopathy of chronic Chagas disease is also discussed. The secreted extracellular vesicles (exosomes) produced for both T. cruzi and infected host cells can play key roles in the host immune response, and those roles are described. Lastly, we describe potential treatments to attenuate the chronic inflammation of the cardiac tissue, designed to improve heart function in chagasic patients.

Dynamics of T Cells Repertoire During Trypanosoma cruzi Infection and its Post-Treatment Modulation

2019 ◽  
Vol 26 (36) ◽  
pp. 6519-6543 ◽  
Author(s):  
Adriana Egui ◽  
Paola Lasso ◽  
Elena Pérez-Antón ◽  
M. Carmen Thomas ◽  
Manuel Carlos López
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Cardiac Tissue ◽  
Acute Infection ◽  
Clinical Status ◽  
Chronic Phase ◽  
Parasite Load ◽  
Chronic Patients ◽  
Cruzi Infection

Chagas disease courses with different clinical phases and has a variable clinical presentation and progression. The acute infection phase mostly exhibits a non-specific symptomatology. In the absence of treatment, the acute phase is followed by a chronic phase, which is initially asymptomatic. This chronic asymptomatic phase of the disease is characterized by a fragile balance between the host’s immune response and the parasite replication. The loss of this balance is crucial for the progression of the sickness. The virulence and tropism of the T. cruzi infecting strain together to the inflammation processes in the cardiac tissue are the main factors for the establishment and severity of the cardiomyopathy. The efficacy of treatment in chronic Chagas disease patients is controversial. However, several studies carried out in chronic patients demonstrated that antiparasitic treatment reduces parasite load in the bloodstream and leads to an improvement in the immune response against the Trypanosoma cruzi parasite. The present review is mainly focused on the cellular patterns associated to the clinical status and the evolution of the disease in chronic patients, as well as the effectiveness of the treatment related to T. cruzi infection control. Therefore, an emphasis is placed on the dynamics of specific-antigens T cell subpopulations, their memory and activation phenotypes, their functionality and their contribution to pathogenesis or disease control, as well as their association with risk of congenital transmission of the parasite.

scholarly journals Genetic Susceptibility to Chagas Disease: An Overview about the Infection and about the Association between Disease and the Immune Response Genes

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Christiane Maria Ayo ◽  
Márcia Machado de Oliveira Dalalio ◽  
Jeane Eliete Laguila Visentainer ◽  
Pâmela Guimarães Reis ◽  
Emília Ângela Sippert ◽  
...  
Keyword(s):  
Immune Response ◽  
Chagas Disease ◽  
Chronic Infection ◽  
Genetic Factors ◽  
Clinical Course ◽  
Clinical Manifestations ◽  
Severity Of Disease ◽  
Host Genetic ◽  
Host Genetic Factors

Chagas disease, which is caused by the flagellate parasiteTrypanosoma cruzi, affects 8–10 million people in Latin America. The disease is endemic and is characterised by acute and chronic phases that develop in the indeterminate, cardiac, and/or gastrointestinal forms. The immune response during humanT. cruziinfection is not completely understood, despite its role in driving the development of distinct clinical manifestations of chronic infection. Polymorphisms in genes involved in the innate and specific immune response are being widely studied in order to clarify their possible role in the occurrence or severity of disease. Here we review the role of classic and nonclassic MHC,KIR, and cytokine host genetic factors on the infection byT. cruziand the clinical course of Chagas disease.

scholarly journals Platelet nitric oxide signalling in heart failure: role of oxidative stress

2011 ◽  
Vol 91 (4) ◽  
pp. 625-631 ◽  
Author(s):  
Ashish Shah ◽  
Gabriella Passacquale ◽  
Eugenia Gkaliagkousi ◽  
James Ritter ◽  
Albert Ferro
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Heart Failure

scholarly journals The role of oxidative/nitrosative stress in pathogenesis of paracetamol-induced toxic hepatitis

2010 ◽  
Vol 63 (11-12) ◽  
pp. 827-832 ◽  
Author(s):  
Tatjana Radosavljevic ◽  
Dusan Mladenovic ◽  
Danijela Vucevic ◽  
Rada Jesic-Vukicevic
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Liver Injury ◽  
Kupffer Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Severe Liver ◽  
Hepatocellular Necrosis

Introduction. Paracetamol is an effective analgesic/antipyretic drug when used at therapeutic doses. However, the overdose of paracetamol can cause severe liver injury and liver necrosis. The mechanism of paracetamol-induced liver injury is still not completely understood. Reactive metabolite formation, depletion of glutathione and alkylation of proteins are the triggers of inhibition of mitochondrial respiration, adenosine triphosphate depletion and mitochondrial oxidant stress leading to hepatocellular necrosis. Role of oxidative stress in paracetamol-induced liver injury. The importance of oxidative stress in paracetamol hepatotoxicity is controversial. Paracetamol induced liver injury cause the formation of reactive oxygen species. The potent sources of reactive oxygen are mitochondria, neutrophils, Kupffer cells and the enzyme xatnine oxidase. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. Role of mitochondria in paracetamol-induced oxidative stress. The production of mitochondrial reactive oxygen species is increased, and the glutathione content is decreased in paracetamol overdose. Oxidative stress in mitochondria leads to mito?chondrial dysfunction with adenosine triphosphate depletion, increase mitochondrial permeability transition, deoxyribonu?cleic acid fragmentation which contribute to the development of hepatocellular necrosis in the liver after paracetamol overdose. Role of Kupffer cells in paracetamol-induced liver injury. Paracetamol activates Kupffer cells, which then release numerous cytokines and signalling molecules, including nitric oxide and superoxide. Kupffer cells are important in peroxynitrite formation. On the other hand, the activated Kupffer cells release anti-inflammatory cytokines. Role of neutrophils in paracetamol-induced liver injury. Paracetamol-induced liver injury leads to the accumulation of neutrophils, which release lysosomal enzymes and generate superoxide anion radicals through the enzyme nicotinamide adenine dinucleotide phosphate oxidase. Hydrogen peroxide, which is influenced by the neutrophil-derived enzyme myeloperoxidase, generates hypochlorus acid as a potent oxidant. Role of peroxynitrite in paracetamol-induced oxidative stress. Superoxide can react with nitric oxide to form peroxynitrite, as a potent oxidant. Nitrotyrosine is formed by the reaction of tyrosine with peroxynitrite in paracetamol hepatotoxicity. Conclusion. Overdose of paracetamol may produce severe liver injury with hepatocellular necrosis. The most important mechanisms of cell injury are metabolic activation of paracetamol, glutathione depletion, alkylation of proteins, especially mitochondrial proteins, and formation of reactive oxygen/nitrogen species.

Role of oxidative stress in left ventricular remodeling and heart failure after myocardial infarction

1999 ◽  
Vol 5 (3) ◽  
pp. 79
Author(s):  
Shintaro Kinugawa ◽  
Hiroyuki Tsutsui ◽  
Tomomi Ide ◽  
Hideo Ustumi ◽  
Nobuhiro Suematsu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

Abstract 814: Atorvastatin Attenuates Oxidative Stress And Improves Neuronal Nitric Oxide Synthase In The Brain Stem Of Heart Failure Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Joseph Francis ◽  
Li Yu ◽  
Anuradha Guggilam ◽  
Srinivas Sriramula ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Brain Stem ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Neuronal Nos ◽  
The Brain

3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the incidence of myocardial infarction independent of their lipid-lowering effects. Nitric oxide (NO) in the central nervous system contributes to cardiovascular regulatory mechanisms. Imbalance between nitric oxide (NO) and superoxide anion (O 2 . − ) in the brain may contribute to enhanced sympathetic drive in heart failure (HF). This study was done to determine whether treatment with atorvastatin (ATS) ameliorates the imbalance between NO and O 2 . − production in the brain stem and contributes to improvement of left ventricular (LV) function. Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery or sham surgery. Subsequently, mice were treated with ATS (10 μg/kg) (MI + ATS), or vehicle (MI + V). After 5 weeks, echocardiography revealed left ventricular dilatation in MI mice. Realtime RT-PCR indicated an increase in the mRNA expression of the LV hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Neuronal NOS (nNOS) and endothelial NOS (eNOS) mRNA expression were significantly reduced, while that of NAD(P)H oxidase subunit (gp91phox) expression was elevated in the brain stem of MI mice. Compared with sham-operated mice, ATS-treated mice showed reduced cardiac dilatation, decreased ANP and BNP in the LV. ATS also reduced gp91phox expression and increased nNOS mRNA expression in the brain stem, while no changes in eNOS and iNOS were observed. Conclusion: These findings suggest that ATS reduces oxidative stress and increases neuronal NOS in the brain stem, and improves left ventricular function in heart failure.

Abstract 125: Perturbation of Mitochondrial Calcium Uniporter Promotes Cardiac Oxidative Stress and Autophagy During Heart Failure

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Sudarsan Rajan ◽  
Santhanam Shanmughapriya ◽  
Dhanendra Tomar ◽  
Zhiwei Dong ◽  
Joseph Y Cheung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Mouse Model ◽  
Atp Depletion ◽  
Regulatory Role ◽  
Mitochondrial Calcium ◽  
Mitochondrial Bioenergetics ◽  
Complex Assembly ◽  
New Findings

Mitochondrial calcium ([Ca 2+ ] m ) is essential for cardiomyocyte viability, and aberration of [Ca 2+ ] m is known to elicit multiple cardiac stress conditions associated with ATP depletion, reactive oxygen species, and mitochondrial permeability transition pore opening, all of which can lead to metabolic stress and the loss of dysfunctional mitochondria by aberrant autophagy. Elucidating the regulatory role of m itochondrial c alcium u niporter (MCU)-mediated [Ca 2+ ] m in modulating cardiac mitochondrial bioenergetics and autophagy has high significance and clinical impact for many pathophysiological processes. [Ca 2+ ] m is exquisitely controlled by the inner mitochondrial membrane uniporter, transporters, regulators and exchangers including MCU, MCUR1, EMRE, MICU1, MICU2 and LETM1. Our recently published findings revealed that Mitochondrial Ca 2+ Uniporter Regulator 1 (MCUR1) serves as a scaffold factor for uniporter complex assembly. We found that deletion of MCUR1 impaired [Ca 2+ ] m uptake, mitochondrial Ca 2+ current ( I MCU ) and mitochondrial bioenergetics and is associated with increased autophagy. Our new findings indicate that the impairment of [Ca 2+ ] m uptake exacerbated autophagy following ischemia-reperfusion (I/R) injury. In support of our mouse model, human failing hearts show that MCUR1 protein levels are markedly decreased and autophagy markers are increased, demonstrating a crucial link between [Ca 2+ ] m uptake and autophagy during heart failure. Additionally, our results reveal that either oxidation or disruption of human MCU Cys-97 (in mouse Cys-96; gain-of-function MCU C96A mutant) produces a conformational change within the N terminal β-grasp fold of MCU which promotes higher-order MCU complex assembly and increased I MCU activity and mitochondrial ROS levels. The results of our studies using a novel cardiac-specific MCUR1-KO model and a constitutively active global MCU C96A KI mouse model (CRISPR-Cas9 genome edited) elucidate the regulatory role of [Ca 2+ ] m in cardiac bioenergetics and autophagy during oxidative stress and myocardial infarction. Thus, targeting assembly and the activity of MCU complex will offer a new potential therapeutic target in the treatment of cardiomyopathy and heart failure.

Abstract 337: Activation of Myocardial AMP-activated Protein Kinase by Metformin Prevents Progression of Heart Failure in Dogs; Involvement of eNOS Activation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hideyuki Sasaki ◽  
Hiroshi Asanuma ◽  
Masashi Fujita ◽  
Hiroyuki Takahama ◽  
Masanori Asakura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Heart Failure ◽  
Cell Death ◽  
Protein Kinase ◽  
Left Ventricular ◽  
Vehicle Group ◽  
Mrna Levels ◽  
Compound C ◽  
Amp Activated Protein Kinase

Background; Several studies have shown that metformin activates AMP-activated protein kinase (AMPK), which mediates potent cardioprotection against ischemia-reperfusion injury. AMPK is also activated in experimental failing myocardium, suggesting that activation of AMPK is beneficial for the pathophysiology of heart failure. We investigated whether metformin prevents oxidative stress-induced cell death in rat cardiomyocytes and attenuates the progression of heart failure in dogs. Methods and Results; The treatment with metformin (10 μmol/L) protected the rat cultured cardiomyocytes against cell death due to H 2 O 2 exposure (50 μmol/L) as indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), TUNEL staining, and flow cytometry. These effects were blunted by an AMPK inhibitor, compound-C (20 μmol/L), suggesting that the activation of AMPK decreased the extent of apoptosis-induced cell death due to H 2 O 2 exposure. Continuous rapid ventricular pacing (230/min for 4 weeks) in dogs caused heart failure and the treatment with metformin (100 mg/kg/day PO, n=8) decreased left ventricular (LV) end-diastolic dimension (32.8±0.4 vs. 36.5±1.0 mm, p< 0.01) and pressure (11.8±1.1 vs. 22±0.9 mmHg, p< 0.01), and increased LV fractional shortening (18.6±1.8 vs. 9.6±0.7 %, p< 0.01) along with enhanced phosphorylation of AMPK and the decreased the number of TUNEL-positive cells of the LV myocardium compared with the vehicle group (n=8). Interestingly, metformin increased the protein and mRNA levels of endothelial nitric oxide synthase of the LV myocardium and plasma nitric oxide levels. Metformin improved the plasma insulin resistance without increased myocardial GLUT-4 translocation. Furthermore, the subcutaneous administration of AICAR (50 mg/kg/every other day), another AMPK activator mediated the equivalent effects to metformin, strengthening the pivotal role of AMPK in reduction of apoptosis and prevention of heart failure. Conclusions; Activation of myocardial AMPK attenuated the oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with eNOS activation. Thus, metformin or AICAR may be applicable as a novel therapy for heart failure.

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