Molecular Endocrinology, Medical Department I, University of Lübeck, Lübeck, Germany.
Epigenetics & Metabolism, Medical Department I, University of Lübeck, Lübeck, Germany.
J Mol Endocrinol. 2019 Apr 1;62(3):91-99. doi: 10.1530/JME-18-0217.
It is well established that thyroid hormones are required for cardiovascular functions; however, the molecular mechanisms remain incompletely understood, especially the individual contributions of genomic and non-genomic signalling pathways. In this study, we dissected how thyroid hormones modulate aortic contractility. To test the immediate effects of thyroid hormones on vasocontractility, we used a wire myograph to record the contractile response of dissected mouse aortas to the adrenergic agonist phenylephrine in the presence of different doses of T3 (3,3',5-triiodothyronine). Interestingly, we observed reduced vasoconstriction under low and high T3 concentrations, indicating an inversed U-shaped curve with maximal constrictive capacity at euthyroid conditions. We then tested for possible genomic actions of thyroid hormones on vasocontractility by treating mice for 4 days with 1 mg/L thyroxine in drinking water. The study revealed that in contrast to the non-genomic actions the aortas of these animals were hyperresponsive to the contractile stimulus, an effect not observed in endogenously hyperthyroid TRβ knockout mice. To identify targets of genomic thyroid hormone action, we analysed aortic gene expression by microarray, revealing several altered genes including the well-known thyroid hormone target gene hairless. Taken together, the findings demonstrate that thyroid hormones regulate aortic tone through genomic and non-genomic actions, although genomic actions seem to prevail in vivo. Moreover, we identified several novel thyroid hormone target genes that could provide a better understanding of the molecular changes occurring in the hyperthyroid aorta.
众所周知，甲状腺激素对于心血管功能是必需的；然而，其分子机制仍不完全清楚，特别是基因组和非基因组信号通路的个体贡献。在这项研究中，我们剖析了甲状腺激素如何调节主动脉的收缩性。为了测试甲状腺激素对血管收缩性的即时影响，我们使用线描记法记录了分离的小鼠主动脉对儿茶酚胺激动剂苯肾上腺素的收缩反应，同时存在不同剂量的 T3（3,3',5-三碘甲状腺原氨酸）。有趣的是，我们观察到在低和高 T3 浓度下血管收缩减少，表明在正常甲状腺状态下存在最大收缩能力的倒 U 形曲线。然后，我们通过在饮用水中用 1 毫克/升甲状腺素处理小鼠 4 天来测试甲状腺激素对血管收缩性的可能基因组作用。研究表明，与非基因组作用相反，这些动物的主动脉对收缩刺激反应过度，而内源性甲状腺功能亢进的 TRβ 敲除小鼠则没有观察到这种作用。为了确定基因组甲状腺激素作用的靶标，我们通过微阵列分析了主动脉的基因表达，发现了几个改变的基因，包括众所周知的甲状腺激素靶基因 hairless。总之，这些发现表明，甲状腺激素通过基因组和非基因组作用调节主动脉张力，尽管基因组作用在体内似乎占主导地位。此外，我们确定了几个新的甲状腺激素靶基因，这可以更好地理解甲状腺功能亢进的主动脉中发生的分子变化。
