TSH通过cAMP/PKA/CREB上调ARRDC2促心肌肥厚的机制研究

多项临床研究表明亚临床甲减（SCH）患者可出现心肌肥厚的病理表现，然而SCH促进心肌肥厚发生发展的具体机制尚不清楚。我们前期研究发现TSH作用于心肌细胞TSHR受体（TSHR）可以显著促进心肌细胞肥大标志物β-MHC的表达。随后应用蛋白质组学进行了差异蛋白筛选，数据分析显示TSH刺激心肌细胞后含抑制蛋白结构域蛋白2（ARRDC2）表达显著升高。同时应用JASPAR数据库分析发现在ARRDC2的启动子区域存在cAMP反应元件（CRE）。因此我们提出假说：TSH与心肌细胞膜上TSHR结合，通过激活cAMP/PKA/CREB通路上调ARRDC2，促进心肌肥厚的发生发展。我们拟通过体内和体外实验进行深入研究，揭示TSH促进心肌肥厚的具体机制，并明确ARRDC2在TSH促心肌肥厚中的作用。研究成果将为临床上对SCH患者进行早期干预从而改善患者预后提供理论依据，具有重要的科学意义和临床价值。

Several clinical studies have shown that some patients who suffer from subclinical hypothyroidism (SCH) have myocardial hypertrophy. However, the specific mechanism by which SCH promotes cardiac hypertrophy is unclear. Our previous study found that TSH significantly promoted the expression of hypertrophic marker β-MHC. Then we used proteomics analysis found that the expression of arrestin domain containing (ARRDC2) was induced by TSH. And one cAMP response element (CRE) site was found in ARRDC2 promoter by using the JASPAR database. Therefore, we propose a hypothesis: TSH up-regulate ARRDC2 expression by acting on the TSHR in cardiomyocyte membranes and stimulating the cAMP/PKA/ CREB pathway, which can promote the development of cardiac hypertrophy. We will perform further study through experiments in vivo and vitro to reveal the specific mechanism of TSH promoting cardiac hypertrophy, and to clarify the role of ARRDC2. The project will provide a theoretical basis for SCH patients who should receive early intervention to improve prognosis. Our findings will have an important social significance and clinical value.