Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/20646
Title: Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy
Authors: Vasconcelos, Juliana Fraga
Meira, Cássio Santana
Silva, Daniela Nascimento
Nonaka, Carolina Kymie Vasques
Daltro, Pâmela Santana
Macambira, Simone Garcia
Domizi, Pablo Daniel
Borges, Valéria Matos
Santos, Ricardo Ribeiro dos
Souza, Bruno Solano de Freitas
Soares, Milena Botelho Pereira
Affilliation: Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Universidade Salvador. Escola de Ciências da Saúde. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Universidade Federal de Bahia. Instituto de Ciências da Saúde. Departamento de Bioquímica e Biofísica. Salvador, BA, Brasil
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Centro de Ciências da Saúde. Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Abstract: Chagas disease cardiomyopathy is a parasite-driven inflammatory disease to which there are no effective treatments. Here we evaluated the therapeutic potential of N,N-dimethylsphingosine(DMS), which blocks the production of sphingosine-1-phosphate(S1P), a mediator of cellular events during inflammatory responses, in a model of chronic Chagas disease cardiomyopathy. DMS-treated, Trypanosoma cruzi-infected mice had a marked reduction of cardiac inflammation, fibrosis and galectin-3 expression when compared to controls. Serum concentrations of galectin-3, IFNγ and TNFα, as well as cardiac gene expression of inflammatory mediators were reduced after DMS treatment. The gene expression of M1 marker, iNOS, was decreased, while the M2 marker, arginase1, was increased. DMS-treated mice showed an improvement in exercise capacity. Moreover, DMS caused a reduction in parasite load in vivo. DMS inhibited the activation of lymphocytes, and reduced cytokines and NO production in activated macrophage cultures in vitro, while increasing IL-1β production. Analysis by qRT-PCR array showed that DMS treatment modulated inflammasome activation induced by T. cruzi on macrophages. Altogether, our results demonstrate that DMS, through anti-parasitic and immunomodulatory actions, can be beneficial in the treatment of chronic phase of T. cruzi infection and suggest that S1P-activated processes as possible therapeutic targets for the treatment of Chagas disease cardiomyopathy.
Keywords: Chagasic Cardiomyopathy
Chagas disease
Inflammatory disease
Trypanosoma cruzi
Treatment
Mice
keywords: Cardiomiopatia chagásica
Doença de Chagas
Doença inflamatória
Trypanosoma cruzi
Tratamento
Ratos
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: VASCONCELOS, J. F. et al. Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy. Scientific Reports, v.7, n. 1, p.6171, 2017.
DOI: 10.1038/s41598-017-06275-z
ISSN: 2045-2322
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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