Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy
Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy
复制标题
DOI：
10.1161/hh1901.096706
复制
发表时间：
2001-09-28
影响因子：
20.1
通讯作者：
Simpson, PC
中科院分区：
文献类型：
--
作者：
Kinugawa, K;Yonekura, K;Simpson, PC
生理性和病理性心肌肥厚患者甲状腺激素(TH)反应基因转录的变化方向相反，包括α-和β-肌球蛋白重链(MyHC)和肌浆网钙-ATPase(SERCA)，TH治疗可以逆转病理性心肌肥厚的分子和功能异常，如压力超负荷。这些发现提示病理性肥大患者存在相对的甲状腺功能减退，但血清TH水平通常正常。我们研究了TH受体(TH受体)β1、α1和α2在病理和生理性大鼠心肌肥厚模型中的调节作用，这些大鼠的TH靶基因α-和β-MyHC和SERCA在甲减和甲亢样改变。2种心肌肥大模型心肌细胞三种受体亚型均下调，表现为甲状腺功能减退、培养中的苯肾上腺素和体内的压力超负荷。在培养和体内运动中，具有甲亢样表型TH(三碘甲腺原氨酸，T3)的模型中，心肌细胞TRBeta1表达上调。在心肌细胞培养中，tR的过度表达或过量的t3，逆转了苯肾上腺素对TH反应的mRNAs和启动子的影响。此外，TRβ1选择性激动剂GC-1处理后，TRβ1亚型与β-MyHC、SERCA和TRβ1转录的功能偶联程度不同，而TRAlpha1与α-MyHC转录的功能偶联程度不同，心肌细胞体积增大。我们认为，Trr亚型在大鼠心肌细胞中具有明显的调控和功能。心肌细胞受体水平的变化可以部分解释生理性和病理性心肌肥厚的特有分子表型。
Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including alpha- and beta -myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) beta1, alpha1, and alpha2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, alpha- and beta -MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TR beta1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TR beta1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TR beta1 to transcription of beta -MyHC, SERCA, and TR beta1, and TR alpha1 to alpha -MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy.