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      Polymorphism in the Alpha Cardiac Muscle Actin 1 Gene Is Associated to Susceptibility to Chronic Inflammatory Cardiomyopathy

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      1 , 2 , 6 , 1 , 2 , 1 , 3 , 4 , 4 , 1 , 2 , 1 , 2 , 1 , 5 , 6 , 6 , 1 , 5 , 5 , 5 , 4 , 4 , 4 , 7 , 1 , 1 , 1 , 3 , 1 , 1 , 2 , 7 , 1 , 2 , 7 , 6 , *
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          Abstract

          Aims

          Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America, and may lead to a life-threatening inflammatory dilated, chronic Chagas cardiomyopathy (CCC). One third of T. cruzi-infected individuals progress to CCC while the others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Since mutations in multiple sarcomeric genes, including alpha-cardiac actin (ACTC1) have been involved in hereditary dilated cardiomyopathy, we investigated the involvement of the ACTC1 gene in CCC pathogenesis.

          Methods and Results

          We conducted a proteomic and genetic study on a Brazilian study population. The genetic study was done on a main cohort including 118 seropositive asymptomatic subjects and 315 cases and the replication was done on 36 asymptomatic and 102 CCC cases. ACTC1 protein and mRNA levels were lower in myocardial tissue from patients with end-stage CCC than those found in hearts from organ donors. Genotyping a case-control cohort of CCC and ASY subjects for all informative single nucleotide polymorphism (SNP) in the ACTC1 gene identified rs640249 SNP, located at the 5’ region, as associated to CCC. Associations are borderline after correction for multiple testing. Correlation and haplotype analysis led to the identification of a susceptibility haplotype. Functional assays have shown that the rs640249A/C polymorphism affects the binding of transcriptional factors in the promoter regions of the ACTC1 gene. Confirmation of the detected association on a larger independent replication cohort will be useful.

          Conclusions

          Genetic variations at the ACTC1 gene may contribute to progression to chronic Chagas Cardiomyopathy among T. cruzi-infected patients, possibly by modulating transcription factor binding to ACTC1 promoter regions.

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          Most cited references43

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          B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction.

          This study sought to determine the prognostic value of B-type natriuretic peptide (BNP) in patients with heart failure with preserved ejection fraction (HFPEF), in comparison to data in HF patients with reduced left ventricular (LV) EF (≤40%). Management of patients with HFPEF is difficult. BNP is a useful biomarker in patients with reduced LVEF, but data in HFPEF are scarce. In this study, 615 patients with mild to moderate HF (mean age 70 years, LVEF 33%) were followed for 18 months. BNP concentrations were measured at baseline and were related to the primary outcome, that is, a composite of all-cause mortality and HF hospitalization, and to mortality alone. The population was divided in quintiles, according to LVEF, and patients with reduced LVEF were compared with those with HFPEF. There were 257 patients (42%) who had a primary endpoint and 171 (28%) who died. BNP levels were significantly higher in patients with reduced LVEF than in those with HFPEF (p < 0.001). BNP was a strong predictor of outcome, but LVEF was not. Importantly, if similar levels of BNP were compared across the whole spectrum of LVEF, and for different cutoff levels of LVEF, the associated risk of adverse outcome was similar in HFPEF patients as in those with reduced LVEF. BNP levels are lower in patients with HFPEF than in patients with HF with reduced LVEF, but for a given BNP level, the prognosis in patients with HFPEF is as poor as in those with reduced LVEF. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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            Chronic Chagas' disease cardiomyopathy patients display an increased IFN-gamma response to Trypanosoma cruzi infection.

            One-third of all Trypanosoma cruzi -infected patients eventually develop chronic Chagas' disease cardiomyopathy (CCC), a particularly lethal inflammatory dilated cardiomyopathy, where parasites are scarce and heart-infiltrating mononuclear cells seem to be the effectors of tissue damage. Since T. cruzi is a major inducer of interleukin-12 production, the role of inflammatory cytokines in the pathogenesis of CCC was investigated. We assayed cytokine production by peripheral blood mononuclear cells (PBMC) from CCC and asymptomatic T. cruzi -infected (ASY) individuals, as well as by T cell lines from endomyocardial biopsies from CCC patients. PBMC from CCC and ASY patients produced higher IFN-gamma levels than normal (N) individuals in response to B13 protein and phytohaemagglutinin PHA; IFN-gamma high responders (> or =1 ng/ml) were 2-3 fold more frequent among CCC patients than ASY individuals. Conversely, IL-4 production in response to the same stimuli was suppressed among T. cruzi -infected patients. The frequency of PHA-induced IFN gammaproducing cells on PBMC was significantly higher among CCC than ASY and N individuals. IFN-gamma and TNF-alpha were produced by ten out of ten PHAstimulated T cell lines from CCC patients; IL-2 and IL-10 were produced by four out of ten and one out of ten lines, respectively; IL-4, IL-1alpha, IL-1beta, IL-6 and IL-12 were undetectable. Our results suggest that CCC and ASY patients may respond differentially to the IFN-gamma-inducing stimulus provided by T. cruzi infection. Given the T(1)-type cytokine profile of heart-infiltrating T cell lines from CCC patients, the ability to mount a vigorous IFN-gamma response may play a role on the differential susceptibility to CCC development. Copyright 2001 Academic Press.
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              The chemokine receptor CCR7 activates in dendritic cells two signaling modules that independently regulate chemotaxis and migratory speed.

              CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a G(i)-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of G(i) and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving G(i) and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                19 December 2013
                : 8
                : 12
                : e83446
                Affiliations
                [1 ]Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil
                [2 ]Institute for Investigation in Immunology (iii), Instituto Nacional de ciencias e tecnologia, São Paulo, São Paulo, Brazil
                [3 ]Laboratory of Immunology, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
                [4 ]Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil
                [5 ]School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
                [6 ]Aix-Marseille Université, Marseille, France
                [7 ]Division of Clinical Immunology and Allergy, University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil
                Universite de Montreal, Canada
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JK ACP ECN CC. Performed the experiments: AFF PCT AK HG AL. Analyzed the data: AFF PCT ECN CC. Contributed reagents/materials/analysis tools: BMI CWP BS LHTW LGN PB FD SA AS ED JAMN MH MS AF EAB ANS AIF RHBS VR ACP. Wrote the manuscript: ECN CC.

                Article
                PONE-D-13-10155
                10.1371/journal.pone.0083446
                3868584
                24367596
                b1c336a7-8906-46c6-823f-d5f86565c1e4
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 March 2013
                : 4 November 2013
                Funding
                This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Aix-Marseille University (Direction des Relations Internationales), the USP-COFECUB program, the ARCUS II PACA Brésil program, CNPq (the Brazilian National Research Council), and FAPESP (São Paulo State Research Funding Agency-Brazil). ECN and CC received support from an international program funded by the French ANR agency and the Brazilian FAPESP agency.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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