Abstract 82: Mnsodtg Mice Exhibit Improved Heart and Mitochondrial Function During Chronic Chagas Disease

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jianjun Wen ◽  
Craig Porter ◽  
David Herndon ◽  
Nisha J Garg
Keyword(s):  
Chagas Disease ◽  
Mitochondrial Function ◽  
Heart Function ◽  
Heart Tissue ◽  
Oxygen Flux ◽  
Wild Type ◽  
Ros Scavenging ◽  
Scavenging Capacity ◽  
The Impact ◽  
Chronic Chagas Disease

Background: We observed that mitochondrial reactive oxygen species (mtROS) plays very important roles in the pregression of chagesic disease (CD). In this study, we utilized genetically-modified mice to scavenge mtROS to investigate the impact of improved ROS scavenging capacity on heart function in CD. Methods and Results: C57BL/6 mice (wild-type, MnSODtg, MnSOD+/-) were infected with Trypanosoma cruzi(Tc). Chronically infected mice (≥120dpi) exhibited a substantial decrease in heart tissue MnSOD gene expression, protein level, enzyme activity and antioxidant level; decrease of heart dysfunction via lower of SV, CO, EF, FS and LVPW,s, and increase of ESV/EDS and LVID;s; enhancement of hypertrophy by increase of IVS, LV mass and areas duo to augmentation of collagen expressions. One of our novel observations was that sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2) lost its role of maintenance of low cytoplasm free calcium and mediated calcium uptake to intracellular store in Tc-induced chronic chagasic disease. Studies of fresh heart slices using O2K confirmed that Tc diminished heart mitochondrial function like decrease of oxygen flux and respiratory control ratio (RCR), which were caused by enhancements of ROS. Myocardial mitochondrial damage was pronounced and associated with a >x% decline in mitochondrial oxygen flux in chronically infected wild-type and MnSOD transgenic mice. Imaging of intact heart for cardiomyocytes and collagen by the nonlinear optical microscopy techniques showed significant increase in collagen (>x0-fold) in chronically infected wild-type mice; while MnSODtg mice exhibited a basal increase in collagen that did not change during chronic phase. Chronically infected MnSODtg mice exhibited a marginal decline in Tc-induced heart function, heart hypertrophy, mitochondrial dysfunction Conclusions: Overexpression of MnSOD inhibited Tc-induced oxidative damage od heart tissue. , suggesting that enhancing the mitochondrial ROS scavenging capacity was beneficial in controlling the inflammatory and oxidative pathology, and cardiac remodeling responses that are hallmarks of chronic Chagas disease.

scholarly journals Autoimmunity in Chagas' heart disease

1995 ◽  
Vol 113 (2) ◽  
pp. 757-766 ◽  
Author(s):  
Edécio Cunha-Neto ◽  
Jorge Kalil
Keyword(s):  
Chagas Disease ◽  
Heart Tissue ◽  
Cross Reactivity ◽  
Autoimmune Response ◽  
Mammalian Host ◽  
Inflammatory Cell Infiltrate ◽  
Cell Infiltrate ◽  
Published Evidence ◽  
Definition Of ◽  
Chronic Chagas Disease

The time scale dissociation between high parasitemia and tissue pathology, allied to the absence of parasites in the heart lesions of chronic Chagas' disease cardiopathy, casted doubt on the direct participation of Trypanosoma cruzi in tissue lesions. Moreover, the heart tissue lesions in chronic Chagas' disease cardiopathy are associated to an inflammatory mononuclear cell infiltrate, presumably the ultimate effectors of tissue damage. It has been hypothesized that the inflammatory cell infiltrate could mediate a delayed hypersensitivity process directed to the heart tissue components, an autoimmune response triggered by immunological cross-reactivity in the course of a protective immune response against some T.cruzi antigen homologous to heart proteins. However, little is known about the efector role of the T cells in the infiltrate, or about the nature of the antigen that lead to their accumulation in tissue. In this paper, we will review the published evidence on autoimmunity and immunological cross-reactivity between T. cruzi and the mammalian host, along with data generated in our laboratory. The definition of the precise role played by autoimmunity in the pathogenesis of Chagas' disease cardiopathy may have important consequences both for immunoprophylaxis and for the therapeutic approach of chronic Chagas' disease.

scholarly journals Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas disease

2020 ◽  
Author(s):  
Danya A. Dean ◽  
Gautham ◽  
Jair L. Siqueira-Neto ◽  
James H. McKerrow ◽  
Pieter C. Dorrestein ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasite Burden ◽  
Heart Tissue ◽  
Blood Transfusions ◽  
Organ Transplants ◽  
Chronic Stage ◽  
Congenital Transmission ◽  
Cardiac Symptoms ◽  
The Impact

AbstractChagas disease (CD) is one of thirteen neglected tropical diseases caused by the parasite Trypanosoma cruzi. CD is a vector-borne disease transmitted by triatomines but CD can also be transmitted through blood transfusions, organ transplants and congenital transmission. While endemic to Latin America, T. cruzi infects 7-8 million people worldwide and can induce severe cardiac symptoms including apical aneurysms, thromboembolisms and arrhythmias during the chronic stage of CD. However, these cardiac clinical manifestations and CD disease pathogenesis are not fully understood. Using spatial metabolomics (chemical cartography), we sought to understand the localized impact of infection on the cardiac metabolome of mice chronically infected with two divergent T. cruzi strains. Our data showed chemical differences in localized cardiac regions upon chronic T. cruzi infection, indicating that parasite infection changes the host metabolome at select sites in chronic CD. These sites were distinct from the sites of highest parasite burden. In addition, we identified acylcarnitines and phosphocholines as discriminatory chemical families within each heart region, comparing infected and uninfected samples. Overall, our study indicated overall and positional metabolic differences common to infection with different T. cruzi strains, and identified select infection-modulated pathways. These results provide further insight into CD pathogenesis and demonstrate the advantage of a spatial perspective to understand infectious disease tropism.Author SummaryChagas disease (CD) is a tropical disease caused by the parasite Trypanosoma cruzi. CD originated in South America; however, there are now 7-8 million people infected worldwide due to population movements. CD is transmitted through a triatomine vector, organ transplants, blood transfusions and congenital transmission. It occurs in two stages, an acute stage (usually asymptomatic) and the chronic stage. Chronic stage CD presents with severe cardiac symptoms such as heart failure, localized aneurysms and cardiomyopathy. Unfortunately, what causes severe cardiac symptoms in some individuals in chronic CD is not fully understood. Therefore, we used liquid chromatography-tandem mass spectrometry to analyze the heart tissue of chronically T. cruzi-infected and uninfected mice, to understand the impact of infection on the tissue metabolome. We identified discriminatory small molecules related to T. cruzi infection. We also determined that regions with the highest parasite burden are distinct from the regions with the largest changes in overall metabolite profile; these locations of high metabolic perturbation provide a molecular mechanism to why localized cardiac symptoms occur in CD. Overall, our work gives insight to chronic cardiac CD symptom development and shapes a framework for novel treatment and biomarker development.

scholarly journals Loss of the Long Non-coding RNA OIP5-AS1 Exacerbates Heart Failure in a Sex-Specific Manner

2021 ◽  
Author(s):  
Aowen Zhuang ◽  
Anna C. Calkin ◽  
Shannen Lau ◽  
Helen Kiriazis ◽  
Daniel G. Donner ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Function ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Heart Function ◽  
Pressure Overload ◽  
Enrichment Analysis ◽  
Heart Tissue ◽  
Gene Set Enrichment Analysis ◽  
Knock Out

AbstractBackgroundLong ncRNAs (lncRNAs) are known to influence numerous biological processes including cellular differentiation and tissue development. They are also implicated in the maintenance, health and physiological function of many tissues including the heart. Indeed, manipulating the expression of specific lncRNAs has been shown to improve pathological cardiac phenotypes such as heart failure. One lncRNA studied in various settings is OIP5-AS1 (also known as 1700020I14Rik and Cyrano), however its role in cardiac pathologies remains mostly uncharacterised.MethodsWe used data generated from FACS sorted murine cardiomyocytes, human iPSC derived cardiomyocytes, as well as heart tissue from various animal models to investigate OIP5-AS1 expression in health and disease. Using CRISPR we engineered a global OIP5-AS1 knock out (KO) mouse model and performed cardiac pressure overload experiments to study heart failure in these animals. RNA-sequencing of left ventricles provided mechanistic insight between WT and KO mice.ResultsWe demonstrate that OIP5-AS1 expression is regulated during cardiac development and cardiac specific pathologies in both rodent and human models. Moreover, we demonstrate that global female OIP5-AS1 KO mice develop exacerbated heart failure, but male mice do not. Transcriptomics and gene set enrichment analysis suggests that OIP5-AS1 may regulate pathways that impact mitochondrial function.ConclusionsOIP5-AS1 is regulated in cardiac tissue and its deletion leads to worsening heart function under pressure overload in female mice. This may be due to impairments in mitochondrial function, highlighting OIP5-AS1 as a gene of interest in sex-specific differences in heart failure.

scholarly journals Predictors of development of cardiac and digestive disorders among patients with indeterminate chronic Chagas Disease

2021 ◽  
Vol 15 (8) ◽  
pp. e0009680
Author(s):  
Erika Alessandra Pellison Nunes da Costa ◽  
Cassiano Victória ◽  
Carlos Magno Castelo Branco Fortaleza
Keyword(s):  
Chagas Disease ◽  
Cox Regression ◽  
Female Gender ◽  
Southeastern Brazil ◽  
Coronary Syndrome ◽  
Final Multivariable Model ◽  
Cardiac Disorders ◽  
Digestive Disorders ◽  
The Impact ◽  
Chronic Chagas Disease

American trypanosomiasis (Chagas disease, CD) affects circa 7 million persons worldwide. While of those persons present the asymptomatic, indeterminate chronic form (ICF), many will eventually progress to cardiac or digestive disorders. We studied a nonconcurrent (retrospective) cohort of patients attending an outpatient CD clinic in Southeastern Brazil, who were admitted while presenting the ICF in the period from 1998 through 2018 and followed until 2019. The outcomes of interest were the progression to cardiac or digestive CD forms. We were also interested in analyzing the impact of Benznidazole therapy on the progression of the disease. Extensive review of medical charts and laboratory files was conducted, collecting data up to year 2019. Demographics (upon inclusion), body mass index, comorbidities (including the Charlson index) and use of Benznidazole were recorded. The outcomes were defined by abnormalities in those test that could not be attributed to other causes. Statistical analysis included univariate and multivariable Cox regression models. Among 379 subjects included in the study, 87 (22.9%) and 100 (26.4%) progressed to cardiac and digestive forms, respectively. In the final multivariable model, cardiac disorders were positively associated with previous coronary syndrome (Hazzard Ratio [HR], 2.42; 95% Confidence Interval [CI], 1.53–3.81) and negatively associated with Benznidazole therapy (HR, 0.26; 95%CI, 0.11–0.60). On the other hand, female gender was the only independent predictor of progression to digestive forms (HR, 1.56; 95%CI, 1.03–2.38). Our results point to the impact of comorbidities on progression do cardiac CD, with possible benefit of the use of Benznidazole.

The Impact of Socioeconomic Conditions on Chronic Chagas Disease Progression

2009 ◽  
Vol 62 (11) ◽  
pp. 1224-1232 ◽  
Author(s):  
Rodolfo Viotti ◽  
Carlos A. Vigliano ◽  
María G. Álvarez ◽  
Bruno E. Lococo ◽  
Marcos A. Petti ◽  
...  
Keyword(s):  
Disease Progression ◽  
Chagas Disease ◽  
Socioeconomic Conditions ◽  
The Impact ◽  
Chronic Chagas Disease

scholarly journals Long-Chain Acyl-Carnitines Interfere with Mitochondrial ATP Production Leading to Cardiac Dysfunction in Zebrafish

2021 ◽  
Vol 22 (16) ◽  
pp. 8468
Author(s):  
Deung-Dae Park ◽  
Bernd M. Gahr ◽  
Julia Krause ◽  
Wolfgang Rottbauer ◽  
Tanja Zeller ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Contractile Function ◽  
Heart Function ◽  
Mitochondrial Morphology ◽  
Zebrafish Embryos ◽  
Cardiac Contractile Function ◽  
Direct Role ◽  
Atp Production ◽  
The Impact ◽  
Long Chain

In the human heart, the energy supplied by the production of ATP is predominately accomplished by ß-oxidation in mitochondria, using fatty acids (FAs) as the primary fuel. Long-chain acylcarnitines (LCACs) are intermediate forms of FA transport that are essential for FA delivery from the cytosol into mitochondria. Here, we analyzed the impact of the LCACs C18 and C18:1 on mitochondrial function and, subsequently, on heart functionality in the in vivo vertebrate model system of zebrafish (Danio rerio). Since LCACs are formed and metabolized in mitochondria, we assessed mitochondrial morphology, structure and density in C18- and C18:1-treated zebrafish and found no mitochondrial alterations compared to control-treated (short-chain acylcarnitine, C3) zebrafish embryos. However, mitochondrial function and subsequently ATP production was severely impaired in C18- and C18:1-treated zebrafish embryos. Furthermore, we found that C18 and C18:1 treatment of zebrafish embryos led to significantly impaired cardiac contractile function, accompanied by reduced heart rate and diminished atrial and ventricular fractional shortening, without interfering with cardiomyocyte differentiation, specification and growth. In summary, our findings provide insights into the direct role of long-chain acylcarnitines on vertebrate heart function by interfering with regular mitochondrial function and thereby energy allocation in cardiomyocytes.

Subtle Impact of Akt1 and Akt3 on Exploratory Behavior in Gene Targeted Mice

2015 ◽  
Vol 223 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Christina Leibrock ◽  
Michael Hierlmeier ◽  
Undine E. Lang ◽  
Florian Lang
Keyword(s):  
Forced Swimming Test ◽  
Open Field Test ◽  
Wild Type ◽  
Average Speed ◽  
Closed Area ◽  
Light Area ◽  
Swimming Test ◽  
The Impact ◽  
Center Area ◽  
Dark Transition

Abstract. The present study explored the impact of Akt1 and Akt3 on behavior. Akt1 (akt1-/-) and Akt3 (akt3-/-) knockout mice were compared to wild type (wt) mice. The akt1-/- mice, akt3-/- mice, and wt mice were similar in most parameters of the open-field test. However, the distance traveled in the center area was slightly but significantly less in akt3-/- mice than in wt mice. In the light/dark transition test akt1-/- mice had significantly lower values than wt mice and akt3-/- mice for distance traveled, number of rearings, rearing time in the light area, as well as time spent and distance traveled in the entrance area. They were significantly different from akt3-/- mice in the distance traveled, visits, number of rearings, rearing time in the light area, as well as time spent, distance traveled, number of rearings, and rearing time in the entrance area. In the O-maze the time spent, and the visits to open arms, as well as the number of protected and unprotected headdips were significantly less in akt1-/- mice than in wt mice, whereas the time spent in closed arms was significantly more in akt1-/- mice than in wt mice. Protected and unprotected headdips were significantly less in akt3-/- mice than in wt mice. In closed area, akt3-/- mice traveled a significantly larger distance at larger average speed than akt1-/- mice. No differences were observed between akt1-/- mice, akt3-/- mice and wt-type mice in the time of floating during the forced swimming test. In conclusion, akt1-/- mice and less so akt3-/ mice display subtle changes in behavior.

scholarly journals Circulating miR-146a as a possible candidate biomarker in the indeterminate phase of Chagas disease

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Martha Alicia Ballinas-Verdugo ◽  
Rogelio Frank Jiménez-Ortega ◽  
Eduardo Martínez-Martínez ◽  
Nancy Rivas ◽  
Erick Abraham Contreras-López ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Extracellular Vesicles ◽  
Bioinformatics Analysis ◽  
Chronic Phase ◽  
Heart Tissue ◽  
Detailed Knowledge ◽  
Total Plasma ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Relevant Finding

Abstract Background Chagas disease is considered important and presents intense inflammatory and fibrotic processes induced by the perpetuation of the parasite in the affected tissues and organs. Therefore, it is necessary to inquire about the host defense and attack mechanisms to have a more detailed knowledge about Chagas disease. MicroRNAs are found in blood, tissues and extracellular vesicles. These small regulators of gene expression are involved in physiological and pathological processes in both mammals and parasites. Several microRNAs have deregulated expression in chagasic heart disease, although little is known about their extracellular expression. Our main objective was to evaluate the involvement of miR-21, miR-146a and miR-155 in several samples from mice infected with the TcI Ninoa strain from the acute and indeterminate phases. We also explored a potential functional association of the selected microRNAs using STRING software. This software identified 23 pathways associated with Trypanosoma cruzi infection. In addition, eleven genes were identified through bioinformatics analysis, and we found that SMAD family member 5 was downregulated in both phases. This gene serves as a mediator in the TGF-β signaling pathway. Thus, forty female mice of the CD1 strain were distributed into 4 groups and the expression levels of miR-21, miR-146a and miR-155 were measured in samples of heart tissue, total plasma and plasma extracellular vesicles by quantitative real-time polymerase chain reaction. Results Overexpression of miR-21, miR-146a and miR-155 was observed in heart and plasma in both phases. Moreover, in extracellular vesicles miR-21 and miR-146a were also overexpressed in the acute phase, whereas in the indeterminate chronic phase we found only miR-146a up-regulated. Conclusions The expression of inflammatory microRNAs miR-21, miR-146a and miR-155 were up-regulated in each of the samples from acutely and chronically infected mice. The relevant finding was that miR-146a was up-regulated in each sample in both phases; therefore, this miRNA could be a possible candidate biomarker in Chagas disease.

scholarly journals Titanium Dioxide Presents a Different Profile in Dextran Sodium Sulphate-Induced Experimental Colitis in Mice Lacking the IBD Risk Gene Ptpn2 in Myeloid Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 772
Author(s):  
Javier Conde ◽  
Marlene Schwarzfischer ◽  
Egle Katkeviciute ◽  
Janine Häfliger ◽  
Anna Niechcial ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Titanium Dioxide ◽  
Genetic Risk ◽  
Intestinal Inflammation ◽  
Sodium Sulphate ◽  
Food Additive ◽  
Wild Type ◽  
Dextran Sodium Sulphate ◽  
Risk Gene ◽  
The Impact

Environmental and genetic factors have been demonstrated to contribute to the development of inflammatory bowel disease (IBD). Recent studies suggested that the food additive; titanium dioxide (TiO2) might play a causative role in the disease. Therefore, in the present study we aimed to explore the interaction between the food additive TiO2 and the well-characterized IBD risk gene protein tyrosine phosphatase non-receptor type 2 (Ptpn2) and their role in the development of intestinal inflammation. Dextran sodium sulphate (DSS)-induced acute colitis was performed in mice lacking the expression of Ptpn2 in myeloid cells (Ptpn2LysMCre) or their wild type littermates (Ptpn2fl/fl) and exposed to the microparticle TiO2. The impact of Ptpn2 on TiO2 signalling pathways and TiO2-induced IL-1β and IL-10 levels were studied using bone marrow-derived macrophages (BMDMs). Ptpn2LysMCre exposed to TiO2 exhibited more severe intestinal inflammation than their wild type counterparts. This effect was likely due to the impact of TiO2 on the differentiation of intestinal macrophages, suppressing the number of anti-inflammatory macrophages in Ptpn2 deficient mice. Moreover, we also found that TiO2 was able to induce the secretion of IL-1β via mitogen-activated proteins kinases (MAPKs) and to repress the expression of IL-10 in bone marrow-derived macrophages via MAPK-independent pathways. This is the first evidence of the cooperation between the genetic risk factor Ptpn2 and the environmental factor TiO2 in the regulation of intestinal inflammation. The results presented here suggest that the ingestion of certain industrial compounds should be taken into account, especially in individuals with increased genetic risk

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