LUDMILA RODRIGUES PINTO FERREIRA CAMARGO
Projetos de Pesquisa
Unidades Organizacionais
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina
7 resultados
Resultados de Busca
Agora exibindo 1 - 7 de 7
- Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways(2013) FRADE, Amanda Farage; PISSETTI, Cristina Wide; IANNI, Barbara Maria; SABA, Bruno; LIN-WANG, Hui Tzu; NOGUEIRA, Luciana Gabriel; BORGES, Ariana de Melo; BUCK, Paula; DIAS, Fabricio; BARON, Monique; FERREIRA, Ludmila Rodrigues Pinto; SCHMIDT, Andre; MARIN-NETO, Jose Antonio; HIRATA, Mario; SAMPAIO, Marcelo; FRAGATA, Abilio; PEREIRA, Alexandre Costa; DONADI, Eduardo; KALIL, Jorge; RODRIGUES, Virmondes; CUNHA-NETO, Edecio; CHEVILLARD, ChristopheBackground: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. 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. Migration of Th1-type T cells play a major role in myocardial damage. Methods: Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects. Results: The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%. Conclusions: Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.
- miRNAs may play a major role in the control of gene expression in key pathobiological processes in Chagas disease cardiomyopathy(2020) LAUGIER, Laurie; FERREIRA, Ludmila Rodrigues Pinto; FERREIRA, Frederico Moraes; CABANTOUS, Sandrine; FRADE, Amanda Farage; NUNES, Joao Paulo; RIBEIRO, Rafael Almeida; BROCHET, Pauline; TEIXEIRA, Priscila Camillo; SANTOS, Ronaldo Honorato Barros; BOCCHI, Edimar A.; BACAL, Fernando; CANDIDO, Darlan da Silva; MASO, Vanessa Escolano; NAKAYA, Helder I.; KALIL, Jorge; CUNHA-NETO, Edecio; CHEVILLARD, ChristopheChronic Chagas disease cardiomyopathy (CCC), an especially aggressive inflammatory dilated cardiomyopathy caused by lifelong infection with the protozoan Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Although chronic myocarditis may play a major pathogenetic role, little is known about the molecular mechanisms responsible for its severity. The aim of this study is to study the genes and microRNAs expression in tissues and their connections in regards to the pathobiological processes. To do so, we integrated for the first time global microRNA and mRNA expression profiling from myocardial tissue of CCC patients employing pathways and network analyses. We observed an enrichment in biological processes and pathways associated with the immune response and metabolism. IFN gamma, TNF and NFkB were the top upstream regulators. The intersections between differentially expressed microRNAs and differentially expressed target mRNAs showed an enrichment in biological processes such as Inflammation, inflammation, Th1/IFN-gamma-inducible genes, fibrosis, hypertrophy, and mitochondrial/oxidative stress/antioxidant response. MicroRNAs also played a role in the regulation of gene expression involved in the key cardiomyopathy-related processes fibrosis, hypertrophy, myocarditis and arrhythmia. Significantly, a discrete number of differentially expressed microRNAs targeted a high number of differentially expressed mRNAs (>20) in multiple processes. Our results suggest that miRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue. This may have a bearing on pathogenesis, biomarkers and therapy. Author summary Chronic Chagas disease cardiomyopathy (CCC), an aggressive dilated cardiomyopathy caused by Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Little is known about the molecular mechanisms responsible for its severity. Authors study the possible role of microRNAs in the regulation of gene expression in relevant pathways and pathobiological processes. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) -small RNAs that can regulate gene expression-associated to severe cardiomyopathy development. The inflammatory mediator Interferon-gamma was the most likely inducer of gene expression in CCC, and most genes belonged to the immune response, fibrosis, hypertrophy and mitochondrial metabolism. A discrete number of differentially expressed mRNAs targeted a high number of differentially expressed mRNAs in multiple processes. Moreover, several pathways had multiple targets regulated by microRNAs, suggesting synergic effect. Results suggest that microRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue.
- MicroRNA Transcriptome Profiling in Heart of Trypanosoma cruzi-Infected Mice: Parasitological and Cardiological Outcomes(2015) NAVARRO, Isabela Cunha; FERREIRA, Frederico Moraes; NAKAYA, Helder I.; BARON, Monique Andrade; VILAR-PEREIRA, Glaucia; PEREIRA, Isabela Resende; SILVA, Ana Maria Goncalves; REAL, Juliana Monte; BRITO, Thales De; CHEVILLARD, Christophe; LANNES-VIEIRA, Joseli; KALIL, Jorge; CUNHA-NETO, Edecio; FERREIRA, Ludmila Rodrigues PintoChagas disease is caused by the parasite Trypanosoma cruzi, and it begins with a short acute phase characterized by high parasitemia followed by a life-long chronic phase with scarce parasitism. Cardiac involvement is the most prominent manifestation, as 30% of infected subjects will develop abnormal ventricular repolarization with myocarditis, fibrosis and cardiomyocyte hypertrophy by undefined mechanisms. Nevertheless, follow-up studies in chagasic patients, as well as studies with murine models, suggest that the intensity of clinical symptoms and pathophysiological events that occur during the acute phase of disease are associated with the severity of cardiac disease observed during the chronic phase. In the present study we investigated the role of microRNAs (miRNAs) in the disease progression in response to T. cruzi infection, as alterations in miRNA levels are known to be associated with many cardiovascular disorders. We screened 641 rodent miRNAs in heart samples of mice during an acute infection with the Colombiana T.cruzi strain and identified multiple miRNAs significantly altered upon infection. Seventeen miRNAs were found significantly deregulated in all three analyzed time points post infection. Among these, six miRNAs had their expression correlated with clinical parameters relevant to the disease, such as parasitemia and maximal heart rate-corrected QT (QTc) interval. Computational analyses identified that the gene targets for these six miRNAs were involved in networks and signaling pathways related to increased ventricular depolarization and repolarization times, important factors for QTc interval prolongation. The data presented here will guide further studies about the contribution of microRNAs to Chagas heart disease pathogenesis.
- Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction (vol 215, pg 387, 2017)(2020) FERREIRA, Ludmila Rodrigues Pinto; FERREIRA, Frederico Moraes; NAKAYA, Helder Imoto; DENG, Xutao; CANDIDO, Darlan da Silva; OLIVEIRA, Lea Campos de; BILLAUD, Jean-Noel; LANTERI, Marion C.; RIGAUD, Vagner Oliveira-Carvalho; SEIELSTAD, Mark; KALIL, Jorge; FERNANDES, Fabio; RIBEIRO, Antonio Luiz Pinho; SABINO, Ester Cerdeira; CUNHA-NETO, Edecio
- Myocardial Infarction-Associated Transcript, a Long Noncoding RNA, Is Overexpressed During Dilated Cardiomyopathy Due to Chronic Chagas Disease(2016) FRADE, Amanda Farage; LAUGIER, Laurie; FERREIRA, Ludmila Rodrigues Pinto; BARON, Monique Andrade; BENVENUTI, Luiz Alberto; TEIXEIRA, Priscila Camillo; NAVARRO, Isabela Cunha; CABANTOUS, Sandrine; FERREIRA, Frederico Moraes; CANDIDO, Darlan da Silva; GAIOTTO, Fabio Antonio; BACAL, Fernando; POMERANTZEFF, Pablo; SANTOS, Ronaldo Honorato Barros; KALIL, Jorge; CUNHA-NETO, Edecio; CHEVILLARD, ChristopheLong noncoding RNAs (lncRNAs) modulate gene expression at the epigenetic, transcriptional, and posttranscriptional levels. Dysregulation of the lncRNA known as myocardial infarction-associated transcript (MIAT) has been associated with myocardial infarction. Chagas disease causes a severe inflammatory dilated chronic cardiomyopathy (CCC). We investigated the role of MIAT in CCC. A whole-transcriptome analysis of heart biopsy specimens and formalin-fixed, paraffin-embedded samples revealed that MIAT was overexpressed in patients with CCC, compared with subjects with noninflammatory dilated cardiomyopathy and controls. These results were confirmed in a mouse model. Results suggest that MIAT is a specific biomarker of CCC.
- Whole-Genome Cardiac DNA Methylation Fingerprint and Gene Expression Analysis Provide New Insights in the Pathogenesis of Chronic Chagas Disease Cardiomyopathy(2017) LAUGIER, Laurie; FRADE, Amanda Farage; FERREIRA, Frederico Moraes; BARON, Monique Andrade; TEIXEIRA, Priscila Camillo; CABANTOUS, Sandrine; FERREIRA, Ludmila Rodrigues Pinto; LOUIS, Laurence; RIGAUD, Vagner Oliveira Carvalho; GAIOTTO, Fabio Antonio; BACAL, Fernando; POMERANTZEFF, Pablo; BOCCHI, Edimar; KALIL, Jorge; SANTOS, Ronaldo Honorato Barros; CUNHA-NETO, Edecio; CHEVILLARD, ChristopheBackground. Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide. Approximately 12 000 deaths attributable to Chagas disease occur annually due to chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection. Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients' myocardium. DNA methylation is the most common modification in the mammalian genome. Methods. We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, compared to control samples from organ donors. Results. In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed. Several of them were related to heart function or to the immune response and had methylation sites in their promoter region. Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes. Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased T-helper 1 cytokine-mediated inflammatory damage in heart. Conclusions. Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC.
- Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction(2017) FERREIRA, Ludmila Rodrigues Pinto; FERREIRA, Frederico Moraes; NAKAYA, Helder Imoto; DENG, Xutao; CNDIDO, Darlan da Silva; OLIVEIRA, Lea Campos de; BILLAUD, Jean-Noel; LANTERI, Marion C.; RIGAUD, Vagner Oliveira-Carvalho; SEIELSTAD, Mark; KALIL, Jorge; FERNANDES, Fabio; RIBEIRO, Antonio Luiz P.; SABINO, Ester Cerdeira; CUNHA-NETO, EdecioChagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects 7 million people in Latin American areas of endemicity. About 30% of infected patients will develop chronic Chagas cardiomyopathy (CCC), an inflammatory cardiomyopathy characterized by hypertrophy, fibrosis, and myocarditis. Further studies are necessary to understand the molecular mechanisms of disease progression. Transcriptome analysis has been increasingly used to identify molecular changes associated with disease outcomes. We thus assessed the whole-blood transcriptome of patients with Chagas disease. Microarray analysis was performed on blood samples from 150 subjects, of whom 30 were uninfected control patients and 120 had Chagas disease (1 group had asymptomatic disease, and 2 groups had CCC with either a preserved or reduced left ventricular ejection fraction [LVEF]). Each Chagas disease group displayed distinct gene expression and functional pathway profiles. The most different expression patterns were between CCC groups with a preserved or reduced LVEF. A more stringent analysis indicated that 27 differentially expressed genes, particularly those related to natural killer (NK)/CD8(+) T-cell cytotoxicity, separated the 2 groups. NK/CD8(+) T-cell cytotoxicity could play a role in determining Chagas disease progression. Understanding genes associated with disease may lead to improved insight into CCC pathogenesis and the identification of prognostic factors for CCC progression.