Functional thyrotropin receptor expression in the ventricle and the effects on ventricular BNP secretion
Functional thyrotropin receptor expression in the ventricle and the effects on ventricular BNP secretion
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心室功能性促甲状腺素受体表达及其对心室 BNP 分泌的影响
DOI：
10.1007/s12020-013-0052-6
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发表时间：
2014-06-01
期刊：
影响因子：
3.7
通讯作者：
Zhao, Jia-Jun
中科院分区：
文献类型：
--
作者：
Huang, Wen;Xu, Jin;Zhao, Jia-Jun
促甲状腺激素(TSH)升高和高胆固醇血症在亚临床甲状腺功能减退症患者中普遍并存，可导致和加重心脏病。然而，TSH是否对心脏功能有直接影响尚不清楚。为了研究促甲状腺激素受体(TSHR)的表达及TSH对心功能的影响，我们对正常大鼠和小鼠的心室组织和甲状腺以及H9c2心肌细胞系进行了分析。结果表明，经PCR、免疫印迹、免疫组织化学和免疫荧光检测，TSHR在转录和蛋白水平均有表达。与野生型(WT)小鼠相比，Tshr−/−小鼠脑室β-MHcmRNA水平及pCREB和HMGCR表达均显著降低(P<0.05)，而血清NT-ProBNP水平与野生型(WT)小鼠无明显差异。同步化后，用不同浓度的TSH刺激H9c2细胞不同时间。促甲状腺激素上调H9c2细胞β-MHC基因表达。环磷酸腺苷(CAMP)的产生和下游信号，如pCREB和HMGCR的表达，以及NT-proBNP的分泌，都以剂量和时间依赖的方式增加。腺酰环化酶抑制剂、蛋白激酶A(PKA)抑制剂和HMGCR抑制剂(均为0.05)可抑制TSH刺激的效应。结果表明，功能性TSHR在心肌细胞中表达，并通过cAMP/PKA/pCREB信号通路介导TSH诱导的BNP分泌和HMGCR上调。我们的发现提示TSH在心力衰竭相关的甲状腺功能减退症中具有潜在的新的病理生理作用。
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 inTshr−/−mice than in wild-type (WT) mice (p< 0.05), but serum NT-proBNP levels were similar between WT andTshr−/−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 (allp< 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.