Inhibition of ER Stress by 2-Aminopurine Treatment Modulates Cardiomyopathy in a Murine Chronic Chagas Disease Model.
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ABSTRACT:
SUBMITTER: Ayyappan JP
PROVIDER: S-EPMC6609105 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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Project description:Background Trypanosoma cruzi is an intracellular parasite that causes debilitating chronic Chagas cardiomyopathy (CCM), for which there is no effective drug or vaccine. Previously, we demonstrated increased cardiac lipid accumulation and endoplasmic reticulum stress in mice with CCM. Increased endoplasmic reticulum stress may lead to uncontrolled SREBP (sterol regulatory element-binding protein) activation and lipotoxicity in the myocardium during the intermediate stage of infection and result in progression to chronic CCM. Therefore, we investigated whether inhibiting SREBP activation modulates CCM progression in T cruzi-infected mice. Methods and Results T cruzi-infected cultured cardiomyocytes (3:1 multiplicity of infection; 24 hours postinfection) were incubated with betulin (3 ?mol/L per mL), an SREBP inhibitor, for 24 hours. Quantitative polymerase chain reaction and Western blotting analyses demonstrated a significant reduction in SREBP activation, lipid biosynthesis, and endoplasmic reticulum stress in betulin-treated infected cells compared with untreated cells. T cruzi infected (103 trypomastigotes of the Brazil strain) Swiss mice were fed a customized diet containing betulin during the intermediate stage (40 days postinfection) until the chronic stage (120 DPI). Cardiac ultrasound imaging and histological and biochemical analyses demonstrated anatomical and functional improvements in betulin-treated, infected mice compared with untreated controls: we observed a significant reduction in cholesterol/fatty acid synthesis that may result in the observed cardiac reduction in cardiac lipid accumulation, mitochondrial and endoplasmic reticulum stress, and ventricular enlargement. Conclusions Our study (in vitro and vivo) demonstrates that inhibition of cardiac SREBP activation reduces cardiac damage during T cruzi infection and modulates CCM in a murine Chagas model.
| S-EPMC7033903 | biostudies-literature
Project description:Infection with Trypanosoma cruzi, the etiologic agent in Chagas disease, may result in heart disease. Over the last decades, Chagas disease endemic areas in Latin America have seen a dietary transition from the traditional regional diet to a Western style, fat rich diet. Previously, we demonstrated that during acute infection high fat diet (HFD) protects mice from the consequences of infection-induced myocardial damage through effects on adipogenesis in adipose tissue and reduced cardiac lipidopathy. However, the effect of HFD on the subsequent stages of infection - the indeterminate and chronic stages - has not been investigated. To address this gap in knowledge, we studied the effect of HFD during indeterminate and chronic stages of Chagas disease in the mouse model. We report, for the first time, the effect of HFD on myocardial inflammation, vasculopathy, and other types of dysfunction observed during chronic T. cruzi infection. Our results show that HFD perturbs lipid metabolism and induces oxidative stress to exacerbate late chronic Chagas disease cardiac pathology.
| S-EPMC6355378 | biostudies-literature
Project description:Current treatments for chronic Chagas cardiomyopathy, a disease with high mortality rates and caused by the protozoan Trypanosoma cruzi, are unsatisfactory. Myocardial inflammation, including endothelial activation, is responsible for the structural and functional damage seen in the chronic phase. The clinical efficacy of benznidazole could be improved by decreasing chronic inflammation. Statins, which have anti-inflammatory properties, may improve the action of benznidazole. Here, the action of simvastatin in a murine model of chronic Chagas cardiomyopathy and the link with the production of the proresolving eicosanoid 15-epi-lipoxin A4, produced by 5-lipoxygenase, are evaluated. Simvastatin decreased the expression of the adhesion molecules E-selectin, intracellular adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule type 1 (VCAM-1) in T. cruzi-infected mice. However, when this drug was administered to 5-lipoxygenase-deficient mice, the anti-inflammatory effect was not observed unless exogenous 15-epi-lipoxin A4 was administered. Thus, in chronic Chagas disease, 5-epi-lipoxin A4 induced by simvastatin treatment could improve the pathophysiological condition of patients by increasing the trypanocidal action of benznidazole.
| S-EPMC5328563 | biostudies-other
Project description:Sigma receptor 1 (?R1), a non-opiate transmembrane protein located on endoplasmic reticulum (ER) and mitochondrial membranes, is considered to be a molecular chaperone. Marked protection against cell death has been observed when ligands for ?R1 have been used in in vitro and in vivo models of retinal cell death. Mice lacking ?R1 (?R1(-/-)) manifest late-onset loss of retinal ganglion cells and retinal electrophysiological changes (after many months). The role of ?R1 in the retina and the mechanisms by which its ligands afford neuroprotection are unclear. We therefore used ?R1(-/-) mice to investigate the expression of ER stress genes (BiP/GRP78, Atf6, Atf4, Ire1?) and proteins involved in apoptosis (BCL2, BAX) and to examine the retinal transcriptome at young ages. Whereas no significant changes occurred in the expression of major ER stress genes (over a period of a year) in neural retina, marked changes were observed in these genes, especially Atf6, in isolated retinal Müller glial cells. BCL2 levels decreased in ?R1(-/-) retina concomitantly with decreases in NFkB and pERK1/2. We postulate that ?R1 regulates ER stress in retinal Müller cells and that the role of ?R1 in retinal neuroprotection probably involves BCL2 and some of the proteins that modify its expression (such as ERK, NF?B). Data from the analysis of the retinal transcriptome of ?R1 null mice provide new insights into the role of ?R1 in retinal neuroprotection.
| S-EPMC3976706 | biostudies-literature
Project description:Chagas disease is caused by Trypanosoma cruzi which is endemic in Latin America. T. cruzi infection results in a latent infection with approximately a third of latently infected patients developing chronic Chagas cardiomyopathy (CCM). CCM is a common cause of cardiomyopathy in endemic regions and has a poor prognosis compared to other cardiomyopathies. The factors responsible for the transition from the asymptomatic indeterminate latent stage of infection to CCM are poorly understood. Our previous studies demonstrated that lipid metabolism and diet are important determinants of disease progression. In the present study, we analyzed various serum metabolomic biomarkers such as acylcarnitines, amino acids, biogenic amines, glycerophospholipids, and sphingolipids in murine models of CCM, where the mice specifically develop either left or right ventricular cardiomyopathy based on the diets fed during the indeterminate stage in a murine model of Chagas disease. Our data provide new insights into the metabolic changes that may predispose patients to CCM and biomarkers that may help predict the risk of developing cardiomyopathy from T. cruzi infection. Author Summary. Chronic Chagas cardiomyopathy (CCM) is a parasitic disease prevalent in Latin America. Currently, no effective drugs or vaccines are available to prevent or cure CCM. The factors involved in the disease severity and progression are poorly understood to design new therapeutic interventions. In order to rapidly identify Chagas patients with a higher risk to develop CCM, a new set of biomarkers specific to Chagas disease is needed. We performed serum metabolomic analyses in chronic T. cruzi-infected mice fed on different diets and identified cardiac ventricular-specific metabolite biomarkers that could define CCM severity. In this paper, we present the results of serum metabolomic analyses and discuss its correlations to the diet-induced metabolic regulations in the pathogenesis of CCM in a murine model of Chagas disease.
| S-EPMC6948343 | biostudies-literature
Project description:Patients with Chagas disease have migrated to cities, where obesity, hypertension and other cardiac risk factors are common.The study included adult patients evaluated by the cardiology service in a public hospital in Santa Cruz, Bolivia. Data included risk factors for T. cruzi infection, medical history, physical examination, electrocardiogram, echocardiogram, and contact 9 months after initial data collection to ascertain mortality. Serology and PCR for Trypanosoma cruzi were performed. Of 394 participants, 251 (64%) had confirmed T. cruzi infection by serology. Among seropositive participants, 109 (43%) had positive results by conventional PCR; of these, 89 (82%) also had positive results by real time PCR. There was a high prevalence of hypertension (64%) and overweight (body mass index [BMI] >25; 67%), with no difference by T. cruzi infection status. Nearly 60% of symptomatic congestive heart failure was attributed to Chagas cardiomyopathy; mortality was also higher for seropositive than seronegative patients (p = 0.05). In multivariable models, longer residence in an endemic province, residence in a rural area and poor housing conditions were associated with T. cruzi infection. Male sex, increasing age and poor housing were independent predictors of Chagas cardiomyopathy severity. Males and participants with BMI </=25 had significantly higher likelihood of positive PCR results compared to females or overweight participants.Chagas cardiomyopathy remains an important cause of congestive heart failure in this hospital population, and should be evaluated in the context of the epidemiological transition that has increased risk of obesity, hypertension and chronic cardiovascular disease.
| S-EPMC2872643 | biostudies-other
Project description:Chagas cardiomyopathy is a parasitic infection caused by Trypanosoma cruzi. Structural and functional abnormalities are the result of direct myocardial damage by the parasite, immunological reactions, dysautonomia, and microvascular alterations. Chronic Chagas cardiomyopathy (CCC) is the most serious and important manifestation of the disease, affecting up to 30% of patients in the chronic phase. It results in heart failure, arrhythmias, thromboembolism, and sudden cardiac death. As in other cardiomyopathies, scar-related reentry frequently results in ventricular tachycardia (VT). The scars typically are located in the inferior and lateral aspects of the left ventricle close to the mitral annulus extending from endocardium to epicardium. The scars may be more prominent in the epicardium than in the endocardium, so epicardial mapping and ablation frequently are required. Identification of late potentials during sinus rhythm and mid-diastolic potentials during hemodynamically tolerated VT are the main targets for ablation. High-density mapping during sinus rhythm can identify late isochronal regions that are then targeted for ablation. Preablation cardiac magnetic resonance imaging with late enhancement can identify potentials areas of arrhythmogenesis. Therapeutic alternatives for VT management include antiarrhythmic drugs and modulation of the cardiac autonomic nervous system.
| S-EPMC8710627 | biostudies-literature
Project description:Changes in metabolic processes play a critical role in the survival or death of cells subjected to various stresses. In the present study, we have investigated the effects of ER (endoplasmic reticulum) stress on cellular metabolism. A major difficulty in studying metabolic responses to ER stress is that ER stress normally leads to apoptosis and metabolic changes observed in dying cells may be misleading. Therefore we have used IL-3 (interleukin 3)-dependent Bak-/-Bax-/- haemopoietic cells which do not die in the presence of the ER-stress-inducing drug tunicamycin. Tunicamycin-treated Bak-/-Bax-/- cells remain viable, but cease growth, arresting in G1-phase and undergoing autophagy in the absence of apoptosis. In these cells, we used NMR-based SIRM (stable isotope-resolved metabolomics) to determine the metabolic effects of tunicamycin. Glucose was found to be the major carbon source for energy production and anabolic metabolism. Following tunicamycin exposure, glucose uptake and lactate production are greatly reduced. Decreased 13C labelling in several cellular metabolites suggests that mitochondrial function in cells undergoing ER stress is compromised. Consistent with this, mitochondrial membrane potential, oxygen consumption and cellular ATP levels are much lower compared with untreated cells. Importantly, the effects of tunicamycin on cellular metabolic processes may be related to a reduction in cell-surface GLUT1 (glucose transporter 1) levels which, in turn, may reflect decreased Akt signalling. These results suggest that ER stress exerts profound effects on several central metabolic processes which may help to explain cell death arising from ER stress in normal cells.
| S-EPMC3072169 | biostudies-literature
Project description:Chronic Chagas cardiomyopathy (CCC) caused by a parasite Trypanosoma cruzi is a life-threatening disease in Latin America, for which there is no effective drug or vaccine. The pathogenesis of CCC is complex and multifactorial. Previously, we demonstrated T. cruzi infected mice lose a significant amount of fat tissue which correlates with progression of CCC. Based on this an investigation was undertaken during both acute and chronic T. cruzi infection utilizing the FAT-ATTAC murine model (that allows modulation of fat mass) to understand the consequences of the loss of adipocytes in the regulation of cardiac parasite load, parasite persistence, inflammation, mitochondrial stress, ER stress, survival, CCC progression and CCC severity. Mice were infected intraperitoneally with 5x104 and 103 trypomastigotes to generate acute and chronic Chagas models, respectively. Ablation of adipocytes was carried out in uninfected and infected mice by treatment with AP21087 for 10 days starting at 15DPI (acute infection) and at 65DPI (indeterminate infection). During acute infection, cardiac ultrasound imaging, histological, and biochemical analyses demonstrated that fat ablation increased cardiac parasite load, cardiac pathology and right ventricular dilation and decreased survival. During chronic indeterminate infection ablation of fat cells increased cardiac pathology and caused bi-ventricular dilation. These data demonstrate that dysfunctional adipose tissue not only affects cardiac metabolism but also the inflammatory status, morphology and physiology of the myocardium and increases the risk of progression and severity of CCC in murine Chagas disease.
| S-EPMC8055007 | biostudies-literature
Project description:A 56-year-old female, who immigrated to the USA from Honduras, presented with worsening shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, and decreased exercise tolerance over the previous 2 months. She was diagnosed 1 year previously with non-ischemic dilated cardiomyopathy and non-sustained monomorphic ventricular tachycardia. An implantable cardioverter defibrillator was placed. Cause for her dilated cardiomyopathy was unknown at that time. On admission, her electrocardiogram showed low voltage complexes, with frequent premature ventricular contractions. Transthoracic two-dimensional echocardiogram (2D ECHO) showed severely reduced ejection fraction of 20%, severe mitral regurgitation with left ventricular (LV) hypokinesis, and inferolateral and inferior wall akinesis. On review of her records, a contrast 2D ECHO from the previous year revealed an aneurysm of the LV apical region. Live three-dimensional (3D) ECHO on her present admission showed persistent LV apical aneurysm. Computed tomography angiogram showed no atherosclerotic lesions. Multiple episodes of non-sustained ventricular tachycardia were recorded on telemetry. Based on these findings, the diagnosis of Chagas cardiomyopathy was entertained. Serological tests for Trypanosoma cruzi antibodies were done and returned positive. We report a case of chronic Chagas cardiomyopathy that was initially missed but ultimately diagnosed based on the finding of LV apical aneurysm. <Learning objective: Chagas cardiomyopathy is becoming increasingly prevalent in non-endemic countries. One hallmark finding associated with Chagas cardiomyopathy is left ventricle apical aneurysm. We were able to identify this finding with transthoracic contrast 2D ECHO and live 3D ECHO.>.
| S-EPMC6281735 | biostudies-literature