Identification of genes related to heart failure using global gene expression profiling of human failing myocardium
Identification of genes related to heart failure using global gene expression profiling of human failing myocardium
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DOI：
10.1016/j.bbrc.2010.01.076
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发表时间：
2010-02-26
影响因子：
3.1
通讯作者：
Kitakaze, Masafumi
中科院分区：
文献类型：
--
作者：
Min, Kyung-Duk;Asakura, Masanori;Kitakaze, Masafumi
尽管心力衰竭的治疗方法多种多样，但仍有必要研究心力衰竭的诊断或治疗靶点。因此，我们开发了不同的方法通过使用传统的微阵列分析来管理心力衰竭。我们分析了12例心力衰竭患者的心肌样本的基因表达谱，并使用临床参数如肺动脉压(PAP)和射血分数(EF)构建了心力衰竭相关基因的数据集。从这12个基因中，我们选择了4个在心脏中高表达的基因，并通过基于文献的搜索来检验它们的新颖性。此外，我们还包括四个G蛋白偶联受体(GPCR)编码基因、三个酶编码基因和一个离子通道蛋白编码基因，以识别用于治疗心力衰竭的药物靶点。在用腺病毒将12个基因导入大鼠心肌细胞进行体外功能筛选后，我们获得了5个候选基因的基因靶向小鼠，即MYLA3、GPR37L1、GPR35、MMP23和NBC1。结果表明，GPR35-KO和GPR35-WT小鼠之间以及GPR37L1-Tg和GPR37L1-KO小鼠之间的收缩压存在显著差异。此外，MYLK3-TG和MYLK3-WT小鼠以及GPR37L1-TG和GPR37L1-KO小鼠之间的心脏重量/体重比也有显著差异。因此，基因芯片分析结合临床参数可以有效地识别新的治疗靶点，以预防或管理心力衰竭。(C)2010 Elsevier Inc.保留所有权利。
Although various management methods have been developed for heart failure, it is necessary to investigate the diagnostic or therapeutic targets of heart failure. Accordingly, we have developed different approaches for managing heart failure by using conventional microarray analyses. We analyzed gene expression profiles of myocardial samples from 12 patients with heart failure and constructed datasets of heart failure-associated genes using clinical parameters such as pulmonary artery pressure (PAP) and ejection fraction (EF). From these 12 genes, we selected four genes with high expression levels in the heart, and examined their novelty by performing a literature-based search. In addition, we included four G-protein-coupled receptor (GPCR)-encoding genes, three enzyme-encoding genes, and one ion-channel protein-encoding gene to identify a drug target for heart failure using in silico microarray database. After the in vitro functional screening using adenovirus transfections of 12 genes into rat cardiomyocytes, we generated gene-targeting mice of five candidate genes, namely, MYLA3, GPR37L1, GPR35, MMP23, and NBC1. The results revealed that systolic blood pressure differed significantly between GPR35-KO and GPR35-WT mice as well as between GPR37L1-Tg and GPR37L1-KO mice. Further, the heart weight/body weight ratio between MYLK3-Tg and MYLK3-WT mice and between GPR37L1-Tg and GPR37L1-KO mice differed significantly. Hence, microarray analysis combined with clinical parameters can be an effective method to identify novel therapeutic targets for the prevention or management of heart failure. (C) 2010 Elsevier Inc. All rights reserved.