Coordinate changes in myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype
Coordinate changes in myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype
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DOI：
10.1007/bf03402039
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发表时间：
2002-11-01
影响因子：
5.7
通讯作者：
Bristow, MR
中科院分区：
文献类型：
--
作者：
Abraham, WT;Gilbert, EM;Bristow, MR
背景：在美国，慢性心力衰竭最常见的原因是继发性或原发性扩张型心肌病(DCM)。DCM表型表现出调节收缩功能和病理性肥大的基因表达的变化。然而，目前尚不清楚这些基因表达的变化是否是疾病的产生或修饰。材料和方法：提供疾病影响基因因果关系证据的一种方法是通过纵向实验设计中的系列测量来定量比较表型变化和基因表达的变化。我们研究了47例特发性DCM患者基因表达变化与表型之间的定量关系。在基线和6个月后的心内膜心肌活检中，我们测量了调节收缩功能的基因(β-肾上腺素能受体、肌浆网钙ATPase、α和β-肌球蛋白重链亚型)或与病理性肥厚相关的基因(β-肌球蛋白重链和心钠素)的mRNA表达，以及β-肾上腺素能受体蛋白的表达。结果：DCM表型的改善与α-肌球蛋白重链基因表达的协同增加和β-肌球蛋白重链基因表达的降低直接相关。相反，表型改变与β(1)或β(2)肾上腺素能受体mRNA或蛋白的表达变化无关，也与肌浆网钙ATPase和心钠素的mRNA表达无关。结论：在人DCM中，表型改变与肌球蛋白重链亚型的变化有选择性地相关。这些数据支持肌球蛋白重链亚型改变有助于人类扩张型心肌病疾病进展的假说。
Background: The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying.Materials and Methods: One approach to providing evidence for cause-effect of a disease-influencing gene is to quantitatively compare changes in phenotype to changes in gene expression by employing serial measurements in a longitudinal experimental design. We investigated the quantitative relationships between changes in gene expression and phenotype n 47 patients with idiopathic DCM. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function (beta-adrenergic receptors, sarcoplasmic reticulum Ca2+ ATPase, and alpha- and beta-myosin heavy chain isoforms) or associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide), plus beta-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction.Results: Improvement in DCM phenotype was directly related to a coordinate increase in alpha- and a decrease in beta-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of beta(1)- or beta(2)-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca2+ ATPase and atrial natriuretic peptide.Conclusion: We conclude that in human DCM, phenotypic modification is selectively associated with myosin heavy chain isoform changes. These data support the hypothesis that myosin heavy chain isoform changes contribute to disease progression in human DCM.