Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor α1
Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor α1
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DOI：
10.1016/j.yjmcc.2005.02.008
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发表时间：
2005-04-01
影响因子：
5
通讯作者：
Westerblad, H
中科院分区：
文献类型：
--
作者：
Tavi, P;Sjögren, M;Westerblad, H
甲状腺激素(TH)对心脏发育和功能的深刻影响是由甲状腺激素受体(TR)α(1)和β(1)介导的，虽然已发现大量的TRβ(1)突变患者，但类似的TRα(1)突变患者尚未被发现。最近产生的具有trα(1)显性负突变的杂合子小鼠(trα(1)+/m小鼠)具有正常的TH水平，这可能阻碍了此类突变患者的发现。我们现在测量从trα(1)+/m小鼠和野生型小鼠(WT)分离的心肌细胞的细胞内钙离子和收缩。TRα(1)+/m心肌细胞的表型与甲状腺功能减退症相似，电压激活的钙瞬变和收缩明显减慢。增加刺激频率(从0.5~3赫兹)或β-肾上腺素能刺激可缩小TRa(1)+/m和WT心肌细胞之间的差异。然而，在trα(1)+/m细胞中，3赫兹刺激使舒张期钙离子显著增加，而β-肾上腺素能刺激在松弛过程中触发自发的钙释放事件。Trα(1)+/m和WT心肌细胞对TH处理的反应均表现为“甲亢”表型，具有更快更大的钙瞬变和收缩。离体心组织中，磷蛋白(PLB)表达增加。总之，分离的trα(1)+/m心肌细胞表现出严重的功能障碍，表现为钙瞬变和收缩明显减慢。(C)2005爱思唯尔有限公司。保留所有权利。
The profound effects of thyroid hormone (TH) on heart development and function are mediated by the thyroid hormone receptors (TR) alpha(1) and beta(1) While numerous patients with TR beta(1) mutations have been identified, patients with similar mutations in TR alpha(1) are yet to be discovered. Recently generated heterozygous mice with a dominant negative mutation in TR alpha(1) (TR alpha(1)+/m mice) have normal TH levels, which may have hampered the discovery of patients with such mutations. We now measure intracellular Ca2+ and contraction in cardiornyocytes isolated from TR alpha(1)+/m mice and wildtype littermates (WT). TR alpha(1)+/m cardiomyocytes showed a phenotype similar to that in hypothyroidism with significant slowing of voltage-activated Ca2+ transients and contractions. Increased stimulation frequency (from 0.5 to 3 Hz) or beta-adrenergic stimulation reduced the differences between TR alpha(1)+/m and WT cardiomyocytes. However, in TR alpha(1)+/m cells stimulation at 3 Hz gave a marked increase in diastolic Ca2+ and beta-adrenergic stimulation triggered spontaneous Ca2+ release events during relaxation. Both TR alpha(1)+/m and WT cardiornyocytes responded to TH treatment by displaying a "hyperthyroid" phenotype with faster and larger Ca2+ transients and contractions. Excised TR alpha(1)+/m hearts showed an increased expression of phospholamban (PLB). In conclusion, isolated TR alpha(1)+/m cardiornyocytes display major dysfunctions with marked slowing of the Ca2+ transients and contractions. (c) 2005 Elsevier Ltd. All rights reserved.