Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jing 5 Road, Jinan, Shandong, 250021, China.
Endocrine. 2014 Jun;46(2):328-39. doi: 10.1007/s12020-013-0052-6. Epub 2013 Sep 26.
Elevated thyrotropin (TSH) and hypercholesterolemia commonly coexist in patients with subclinical hypothyroidism, which can cause and aggravate heart disease. However, it is unclear whether TSH has a direct effect on cardiac function. To determine the expression of the thyrotropin receptor (TSHR) and the effects of TSH on ventricular function, we analyzed the ventricular tissues and thyroid glands from normal rats and mice and the H9c2 cardiomyocyte cell line. The results revealed that TSHR was expressed at the transcriptional and protein levels by PCR, immunoblotting, immunohistochemistry and immunofluorescence. The mRNA levels of β-MHC and the expression of pCREB and HMGCR in the ventricle were significantly lower in Tshr (-/-) mice than in wild-type (WT) mice (p < 0.05), but serum NT-proBNP levels were similar between WT and Tshr (-/-) mice. After synchronization, H9c2 cells were stimulated with several concentrations of TSH for various time periods. TSH up-regulated β-MHC mRNA expression in H9c2 cells. Cyclic adenosine monophosphate (cAMP) production and downstream signaling, such as pCREB and HMGCR expression and NT-proBNP secretion, increased in dose- and time-dependent manners. The TSH-stimulated effects were suppressed by an adenylyl cyclase inhibitor, a protein kinase A (PKA) inhibitor and HMGCR inhibitors (all p < 0.05). The data indicate functional TSHR is expressed in ventricular myocytes and mediates TSH-induced BNP secretion and HMGCR up-regulation through the cAMP/PKA/pCREB signaling pathway. Our findings suggest a potentially novel pathophysiological role of TSH in heart failure-associated hypothyroidism.
促甲状腺激素（TSH）升高和高胆固醇血症常并存于亚临床甲状腺功能减退症患者中，可导致和加重心脏病。然而，促甲状腺激素（TSH）是否对心脏功能有直接影响尚不清楚。为了确定促甲状腺激素受体（TSHR）的表达以及 TSH 对心室功能的影响，我们分析了正常大鼠、小鼠和 H9c2 心肌细胞系的心室组织和甲状腺组织。结果显示，通过 PCR、免疫印迹、免疫组化和免疫荧光，TSHR 在转录和蛋白水平上均有表达。与野生型（WT）小鼠相比，Tshr（-/-）小鼠的心室β-MHCmRNA 水平和 pCREB 和 HMGCR 的表达明显降低（p < 0.05），但 WT 和 Tshr（-/-）小鼠的血清 NT-proBNP 水平相似。同步后，用几种浓度的 TSH 刺激 H9c2 细胞不同时间。TSH 上调 H9c2 细胞中β-MHC mRNA 的表达。cAMP 产物及其下游信号，如 pCREB 和 HMGCR 的表达和 NT-proBNP 的分泌，呈剂量和时间依赖性增加。TSH 刺激作用被腺苷酸环化酶抑制剂、蛋白激酶 A（PKA）抑制剂和 HMGCR 抑制剂抑制（均 p < 0.05）。这些数据表明功能性 TSHR 在心室肌细胞中表达，并通过 cAMP/PKA/pCREB 信号通路介导 TSH 诱导的 BNP 分泌和 HMGCR 上调。我们的研究结果表明 TSH 在心力衰竭相关甲状腺功能减退症中具有潜在的新型病理生理作用。
