Institute for Experimental Endocrinology, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany.
Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany.
Thyroid. 2024 Jun;34(6):796-805. doi: 10.1089/thy.2023.0638. Epub 2024 Apr 8.
Thyroid hormones regulate cardiac functions mainly through direct actions in the heart and by binding to the thyroid hormone receptor (TR) isoforms α1 and β. While the role of the most abundantly expressed isoform, TRα1, is widely studied and well characterized, the role of TRβ in regulating heart functions is still poorly understood, primarily due to the accompanying elevation of circulating thyroid hormone in TRβ knockout mice (TRβ-KO). However, their hyperthyroidism is ameliorated at thermoneutrality, which allows studying the role of TRβ without this confounding factor. Here, we noninvasively monitored heart rate in TRβ-KO mice over several days using radiotelemetry at different housing temperatures (22°C and 30°C) and upon 3,3',5-triiodothyronine (T3) administration in comparison to wild-type animals. TRβ-KO mice displayed normal average heart rate at both 22°C and 30°C with only minor changes in heart rate frequency distribution, which was confirmed by independent electrocardiogram recordings in freely-moving conscious mice. Parasympathetic nerve activity was, however, impaired in TRβ-KO mice at 22°C, and only partly rescued at 30°C. As expected, oral treatment with pharmacological doses of T3 at 30°C led to tachycardia in wild-types, accompanied by broader heart rate frequency distribution and increased heart weight. The TRβ-KO mice, in contrast, showed blunted tachycardia, as well as resistance to changes in heart rate frequency distribution and heart weight. At the molecular level, these observations were paralleled by a blunted cardiac mRNA induction of several important genes, including the pacemaker channels and , as well as . The phenotyping of TRβ-KO mice conducted at thermoneutrality allows novel insights on the role of TRβ in cardiac functions in the absence of the usual confounding hyperthyroidism. Even though TRβ is expressed at lower levels than TRα1 in the heart, our findings demonstrate an important role for this isoform in the cardiac response to thyroid hormones.
甲状腺激素主要通过在心脏中的直接作用以及与甲状腺激素受体 (TR) 异构体 α1 和 β 的结合来调节心脏功能。虽然最丰富表达的异构体 TRα1 的作用得到了广泛的研究和充分的表征，但 TRβ 在调节心脏功能中的作用仍知之甚少，主要是由于 TRβ 敲除小鼠 (TRβ-KO) 中循环甲状腺激素水平升高。然而，它们在热中性时的甲状腺功能亢进得到改善，这使得在没有这种混杂因素的情况下研究 TRβ 的作用成为可能。在这里，我们使用无线电遥测术在不同的环境温度（22°C 和 30°C）下以及在给予三碘甲状腺原氨酸 (T3) 后，非侵入性地监测了几天内 TRβ-KO 小鼠的心率，并与野生型动物进行了比较。TRβ-KO 小鼠在 22°C 和 30°C 下的平均心率正常，心率频率分布只有微小变化，这通过在自由活动的清醒小鼠中进行的独立心电图记录得到了证实。然而，TRβ-KO 小鼠的副交感神经活动在 22°C 时受损，仅在 30°C 时部分恢复。正如预期的那样，在 30°C 下用药理学剂量的 T3 口服治疗导致野生型动物的心动过速，伴随着更广泛的心率频率分布和增加的心脏重量。相比之下，TRβ-KO 小鼠的心动过速减弱，以及对心率频率分布和心脏重量变化的抵抗力增强。在分子水平上，这些观察结果与心脏中几个重要基因的 mRNA 诱导减弱相平行，包括起搏通道 和 ，以及 。在热中性条件下对 TRβ-KO 小鼠进行表型分析，可以在没有通常混杂的甲状腺功能亢进的情况下，对 TRβ 在心脏对甲状腺激素反应中的作用有新的认识。尽管 TRβ 在心脏中的表达水平低于 TRα1，但我们的发现表明该异构体在心脏对甲状腺激素的反应中具有重要作用。
