Cardiac gene expression profiling provides evidence for cytokinopathy as a molecular mechanism in Chagas' disease cardiomyopathy
Cardiac gene expression profiling provides evidence for cytokinopathy as a molecular mechanism in Chagas' disease cardiomyopathy
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DOI：
10.1016/s0002-9440(10)62976-8
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发表时间：
2005-08-01
影响因子：
6
通讯作者：
Liew, CC
中科院分区：
文献类型：
--
作者：
Cunha-Neto, E;Dzao, VJ;Liew, CC
慢性恰加斯病心肌病是拉丁美洲充血性心力衰竭的主要原因，影响300多万人。查加斯心肌病比其他心肌病更具侵袭性，但对其严重性的分子机制知之甚少。我们对人类恰加斯病心肌病和扩张型心肌病的基因表达谱进行了表征，以确定选择性疾病途径和潜在的治疗靶点。我们定制的cDNA微阵列（RT-PCR芯片）和实时逆转录聚合酶链反应分析表明，免疫反应，脂质代谢和线粒体氧化磷酸化基因选择性上调在测试查加斯心肌病患者的心肌组织。干扰素（IFN）-γ诱导基因占查加斯心肌病心肌组织中特异性上调基因的15%，表明IFN-γ信号传导的重要性。为了评估IFN-γ是否可以直接调节心肌细胞基因表达，我们将胎鼠心肌细胞暴露于IFN-γ和IFN-γ诱导的趋化因子单核细胞趋化蛋白-1。心房利钠因子的表达增加15倍，而IFN-γ和单核细胞趋化蛋白-1的组合增加心房利钠因子的表达400倍。我们的研究结果表明IFN-γ和趋化因子信号可能直接上调心肌细胞病理性肥大相关基因的表达，这可能导致心力衰竭。因此，IFN-γ和其他细胞因子途径可能是查加斯心肌病的新治疗靶点。
Chronic Chagas' disease cardiomyopathy is a leading cause of congestive heart failure in Latin America, affecting more than 3 million people. Chagas' cardiomyopathy is more aggressive than other cardiomyopathies, but little is known of the molecular mechanisms responsible for its severity. We characterized gene expression profiles of human Chagas'cardiomyopathy and dilated cardiomyopathy to identify selective disease pathways and potential therapeutic targets. Both our customized cDNA microarray (Cardiochip) and real-time reverse transcriptase-polymerase chain reaction analysis showed that immune response, lipid metabolism, and mitochondrial oxidative phosphorylation genes were selectively upregulated in myocardial tissue of the tested Chagas' cardiomyopathy patients. Interferon (IFN)-gamma-inducible genes represented 15% of genes specifically upregulated in Chagas' cardiomyopathy myocardial tissue, indicating the importance of IFN-gamma signaling. To assess whether IFN-gamma can directly modulate cardiomyocyte gene expression, we exposed fetal murine cardiomyocytes to IFN-gamma and the IFN-gamma-inducible chemokine monocyte chemoattractant protein-1. Atrial natriuretic factor expression increased 15-fold in response to IFN-gamma whereas combined IFN-gamma and monocyte chemoattractant protein-1 increased atrial natriuretic factor expression 400-fold. Our results suggest IFN-gamma and chemokine signaling may directly up-regulate cardiomyocyte expression of genes involved in pathological hypertrophy, which may lead to heart failure. IFN-gamma and other cytokine pathways may thus be novel therapeutic targets in Chagas' cardiomyopathy.