■已知甲状腺激素(THs)对心血管系统具有各种作用。然而,TH水平对已有心脏疾病的影响尚不清楚.由于动脉高血压或主动脉瓣狭窄和衰老引起的压力超负荷是结构和功能异常以及随后的心力衰竭发展的主要危险因素。这里,我们评估了适应性不良心肌肥厚和横向主动脉缩窄(TAC)引起的心功能不全的老年小鼠对TH水平改变的敏感性。
■12月龄的小鼠在诱导左心室压力超负荷后4周接受TAC并在饮用水中接受T4或抗甲状腺药物。
■老年小鼠的T4过量或剥夺对心脏功能没有或仅有很小的影响(缩短分数),心脏重塑(心脏壁厚,心脏重量,心肌细胞大小,凋亡,和间质纤维化),和死亡率。这是令人惊讶的,因为T4过量或剥夺显著改变了年轻8周龄小鼠的TAC后的结果。在年轻和老年小鼠之间比较脱碘酶(Dio)2和3以及TH受体α(TRα)1和显性负向作用同工型TRα2的基因表达,发现老年小鼠表现出更高的TRα2和Dio3表达,而Dio2的表达与年轻小鼠相比降低。Dio2和3表达的这些变化可能导致12月龄小鼠心脏中TH的可用性降低,并伴随着较高的TRα作用降低。
■总之,我们的研究表明,低和高TH可利用度对已有压力诱发心脏损伤的老年小鼠的心脏功能和重塑影响不大.这一观察似乎是脱碘酶和TRα亚型表达改变的结果,因此表明,即使心血管风险随着年龄的增长而增加,在某些条件下,对TH应力的反应可能会减弱。
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.