Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Cardiovascular Pharmacology, Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
Front Endocrinol (Lausanne). 2024 Feb 22;15:1339741. doi: 10.3389/fendo.2024.1339741. eCollection 2024.
Thyroid hormones (THs) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases is still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC).
Mice at the age of 12 months underwent TAC and received T4 or anti-thyroid medication in drinking water over the course of 4 weeks after induction of left ventricular pressure overload.
T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis, and interstitial fibrosis), and mortality. This is surprising because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. Comparing the gene expression of deiodinases (Dio) 2 and 3 and TH receptor alpha (TRα) 1 and the dominant-negative acting isoform TRα2 between young and aged mice revealed that aged mice exhibited a higher expression of TRα2 and Dio3, while expression of Dio2 was reduced compared with young mice. These changes in Dio2 and 3 expressions might lead to reduced TH availability in the hearts of 12-month-old mice accompanied by reduced TRα action due to higher TRα2.
In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure-induced cardiac damage. This observation seems to be the result of an altered expression of deiodinases and TRα isoforms, thus suggesting that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions.
甲状腺激素（THs）对心血管系统有多种影响。然而，TH 水平对已存在的心脏疾病的影响尚不清楚。动脉高血压或主动脉瓣狭窄引起的压力超负荷以及衰老都是导致结构和功能异常以及随后心力衰竭的主要危险因素。在这里，我们评估了改变的 TH 水平在年龄较大的小鼠中的敏感性，这些小鼠存在由横主动脉缩窄（TAC）引起的适应性心脏肥大和心脏功能障碍。
12 个月大的小鼠接受 TAC 手术，并在左心室压力超负荷后 4 周内通过饮用水给予 T4 或抗甲状腺药物。
在老年小鼠中，T4 过多或缺乏对心脏功能（缩短分数）、心脏重构（心脏壁厚度、心脏重量、心肌细胞大小、细胞凋亡和间质纤维化）和死亡率没有或只有很小的影响。这令人惊讶，因为 T4 过多或缺乏在年轻的 8 周龄小鼠中显著改变了 TAC 后的结果。比较年轻和老年小鼠的脱碘酶（Dio）2 和 3 以及甲状腺激素受体α（TRα）1 和显性负性作用的同工型 TRα2 的基因表达表明，老年小鼠表现出更高的 TRα2 和 Dio3 表达，而与年轻小鼠相比，Dio2 的表达减少。这些 Dio2 和 3 表达的变化可能导致 12 个月大的小鼠心脏中的 TH 可用性降低，并由于更高的 TRα2 导致 TRα 作用降低。
总之，我们的研究表明，在存在压力诱导的心脏损伤的老年小鼠中，低和高 TH 可用性对心脏功能和重构的影响较小。这种观察似乎是脱碘酶和 TRα 同工型表达改变的结果，因此表明，尽管随着年龄的增长心血管风险增加，但在某些情况下，对 TH 应激的反应可能会减弱。
