Ferreira Ludmila Rodrigues Pinto, Frade Amanda Farage, Santos Ronaldo Honorato Barros, Teixeira Priscila Camillo, Baron Monique Andrade, Navarro Isabela Cunha, Benvenuti Luiz Alberto, Fiorelli Alfredo Inácio, Bocchi Edimar Alcides, Stolf Noedir Antonio, Chevillard Christophe, Kalil Jorge, Cunha-Neto Edecio
Laboratory of Immunology, Heart Institute (InCor), University of São Paulo, School of Medicine, São Paulo, Brazil; Division of Clinical Immunology and Allergy, University of São Paulo, School of Medicine, São Paulo, Brazil; Institute for Investigation in Immunology (iii), INCT, 05403-001, São Paulo, Brazil.
Division of Surgery, Heart Institute (InCor), University of São Paulo, School of Medicine, São Paulo, Brazil.
Int J Cardiol. 2014 Aug 20;175(3):409-17. doi: 10.1016/j.ijcard.2014.05.019. Epub 2014 May 17.
BACKGROUND/METHODS: Chagas disease is caused by an intracellular parasite, Trypanosoma cruzi, and it is a leading cause of heart failure in Latin America. The main clinical consequence of the infection is the development of a Chronic Chagas disease Cardiomyopathy (CCC), which is characterized by myocarditis, hypertrophy and fibrosis and affects about 30% of infected patients. CCC has a worse prognosis than other cardiomyopathies, like idiopathic dilated cardiomyopathy (DCM). It is well established that myocardial gene expression patterns are altered in CCC, but the molecular mechanisms underlying these differences are not clear. MicroRNAs are recently discovered regulators of gene expression, and are recognized as important factors in heart development and cardiovascular disorders (CD). We analyzed the expression of nine different miRNAs in myocardial tissue samples of CCC patients in comparison to DCM patients and samples from heart transplant donors. Using the results of a cDNA microarray database on CCC and DCM myocardium, signaling networks were built and nodal molecules were identified.
We observed that five miRNAs were significantly altered in CCC and three in DCM; importantly, three miRNAs were significantly reduced in CCC as compared to DCM. We observed that multiple gene targets of the differentially expressed miRNAs showed a concordant inverse expression in CCC. Significantly, most gene targets and involved networks belong to crucial disease-related signaling pathways.
These results suggest that miRNAs may play a major role in the regulation of gene expression in CCC pathogenesis, with potential implication as diagnostic and prognostic tools.
背景/方法：恰加斯病由细胞内寄生虫克氏锥虫引起，是拉丁美洲心力衰竭的主要病因。感染的主要临床后果是慢性恰加斯病性心肌病（CCC）的发展，其特征为心肌炎、心肌肥厚和纤维化，约30%的感染患者会受影响。与其他心肌病如特发性扩张型心肌病（DCM）相比，CCC的预后更差。已明确在CCC中心肌基因表达模式发生改变，但这些差异背后的分子机制尚不清楚。微小RNA是最近发现的基因表达调节因子，被认为是心脏发育和心血管疾病（CD）中的重要因素。我们分析了CCC患者心肌组织样本中9种不同微小RNA的表达，并与DCM患者及心脏移植供体的样本进行比较。利用CCC和DCM心肌的cDNA微阵列数据库结果，构建了信号网络并鉴定了节点分子。
我们观察到CCC中有5种微小RNA显著改变，DCM中有3种；重要的是，与DCM相比，CCC中有3种微小RNA显著降低。我们观察到差异表达微小RNA的多个基因靶点在CCC中呈现一致的反向表达。值得注意的是，大多数基因靶点和相关网络属于关键的疾病相关信号通路。
这些结果表明微小RNA可能在CCC发病机制中的基因表达调控中起主要作用，具有作为诊断和预后工具的潜在意义。
