Signaling pathways responsible for fetal gene induction in the failing human heart - Evidence for altered thyroid hormone receptor gene expression
Signaling pathways responsible for fetal gene induction in the failing human heart - Evidence for altered thyroid hormone receptor gene expression
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DOI：
10.1161/01.cir.103.8.1089
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发表时间：
2001-02-27
期刊：
影响因子：
37.8
通讯作者：
Bristow, MR
中科院分区：
文献类型：
--
作者：
Kinugawa, K;Minobe, WA;Bristow, MR
背景-我们之前已经证明，在衰竭的人类心脏中发生的肌球蛋白重链(MHC)亚型的变化类似于啮齿动物心肌对甲状腺功能减退的反应模式。由于这些患者的甲状腺激素状态通常在正常范围内，我们假设衰竭/肥厚的人类心肌可能由于甲状腺激素受体(TRs)表达的改变而在甲状腺激素信号转导方面存在缺陷。方法和结果-为了验证这一假设，我们使用核糖核酸酶保护试验来检测与年龄匹配的对照组相比，α-MHC表达降低而β-MHC表达增加的衰竭左心室中甲状腺激素受体的基因表达水平。我们检测到人左心室组织中的三种受体-α(1)、-α(2)和-β(1)亚型的表达，在衰竭的左心室中，受体-α(1)表达下调，而不结合甲状腺激素但抑制连接受体反应的剪接变异体--受体-α(2)表达增加。两组患者皮质醇受体β(1)的表达水平无显著差异。线性回归分析显示，tr-α(1)和-α(2)的表达水平分别与α-MHC的表达水平呈正相关和负相关。结论-我们得出结论：tr-α(1)的减少和tr-α(2)的增加可能导致心脏局部甲状腺激素信号的减弱，由此产生的组织特异性甲状腺功能减退可能是导致人衰竭的心脏中胎儿基因表达的分子机制之一。
Background-We have previously demonstrated that changes in myosin heavy chain (MHC) isoforms that occur in failing human hearts resemble the pattern produced in rodent myocardium in response to hypothyroidism. Because thyroid hormone status is usually within normal limits in these patients, we hypothesized that failing/hypertrophied human myocardium might have a defect in thyroid hormone signaling due to alterations in expression of thyroid hormone receptors (TRs).Methods and Results-To examine this hypothesis, we used RNase protection assay to measure mRNA levels of TRs in failing left ventricles that exhibited a fetal pattern of gene expression, ie, decreased expression of alpha -MHC with increased beta -MHC expression compared with left ventricles from age-matched controls. We detected expression of TR-alpha (1), -alpha (2), and -beta (1) isoforms in human left ventricles, In failing left ventricles, TR-alpha (1) was downregulated, whereas TR-alpha (2), a splice variant that does not bind thyroid hormone but inhibits responses to liganded TRs, was increased. Expression levels of TR-beta (1) did not differ significantly between the 2 groups. According to linear regression analysis, expression levels of TR-alpha (1) and -alpha (2) were positively and negatively correlated with those of alpha -MHC, respectively.Conclusions-We conclude that decreases in TR-alpha (1) and increases in TR-alpha (2) may lead to local attenuation of thyroid hormone signaling in the railing human heart and that the resulting tissue-specific hypothyroidism is a candidate for the molecular mechanism that induces fetal gene expression in the failing human ventricle.