Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor α or β
Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor α or β
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DOI：
10.1210/en.142.2.544
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发表时间：
2001-02-01
期刊：
影响因子：
4.8
通讯作者：
Dillmann, WH
中科院分区：
文献类型：
--
作者：
Gloss, B;Trost, SU;Dillmann, WH
心肌细胞表达两种甲状腺激素受体(T(3)Rs)，即T3Rα和T3Rβ。然而，哪种异构体在T-3诱导的心功能改变中起作用仍不清楚。在这里，我们使用单独的T3R亚型基因敲除(KO)小鼠来研究T3Rα和T3Rβ在心脏中的作用。我们的发现表明，编码参与动作电位复极的K+通道的钾通道基因，如Kv4.2和mink，是T3Rα的靶标。两者都明显地受到甲状腺状况的调节。最近发现的环核苷酸门控通道HCN2和HCN4是T3Rα的靶标，在正常甲状腺T3RβKO中没有变化。然而，这些转录本对T-3信号改变伴随着T3RαKO和甲状腺功能低下动物的心动过缓以及甲状腺功能亢进T3RβKO小鼠的心动过速有显著的反应。SERCA2a和肌球蛋白是T-3调节的，也是T3Rα的靶标，αKO动物的乳头肌表现出较慢的力量发育速度。由于甲状腺功能正常的T3RβKO小鼠没有明显的心脏效应，我们测定了心脏中T3Rα和T3Rβ的信使RNA水平。我们发现，T3Rβ与T3Rα1的比例为1：3。我们的结论是，T-3调节的心脏表型主要是由T3Rα介导的，心脏中T3Rα的缺失不能被T3Rβ所补偿。
Cardiac myocytes express the two thyroid hormone receptors (T(3)Rs), T3R alpha and T3R beta. However, which isoform contributes to specific, T-3-induced alterations of cardiac function remains unclear. Here, we used individual T3R isoform knockout (KO) mice to study the effects of T3R alpha and T3R beta in the heart. Our findings indicate that potassium channel genes that code for K+ channels involved in action potential repolarization, Like KV 4.2 and minK, are T3R alpha targets. Both are markedly regulated by thyroid status. The recently identified cyclic nucleotide-gated channels, HCN2 and HCN4, are targets of T3R alpha and are unchanged in a euthyroid T3R beta KO. However, these transcripts respond markedly to altered T-3 signaling concomitant with bradycardia in T3R alpha KO and hypothyroid animals, as well as tachycardia in hyperthyroid T3R beta KO mice. SERCA2a and myosins are T-3 regulated and were also targets of T3R alpha, and the papillary muscles of alpha KO animals showed a slowed rate of force development. Because of the absence of significant cardiac effects in euthyroid T3R beta KO mice, we determined messenger RNA levels for both T3R alpha and T3R beta in the heart. We found that T3R beta is present at a 1:3 ratio to T3R alpha1. We conclude that the cardiac phenotype regulated by T-3 is predominantly mediated by T3R alpha and that the lack of T3R alpha cannot be compensated by T3R beta in the heart.