心血管疾病已经成为威胁人类健康的杀手之一，负荷性的心肌肥大最终将带来一系列心血管疾病。因此，了解心肌肥大产生的分子机理及其信号转导通路的调控，有助于我们预防和治疗心血管疾病。作为核受体，TR3在细胞凋亡和血糖调控中发挥着重要作用，但是，TR3是否参与心肌细胞肥大的调控还没有任何报道。最近，吴乔课题组通过动物实验模型、分子细胞生物学实验和临床病例分析，证实了TR3通过调控mTOR信号通路影响心肌细胞大小，结果导致心肌细胞肥大。该研究成果刚刚网上发表在国际SCI刊物EMBO Molecular Medicine。第一作者为生科院的王荣浩、何建平、罗杰以及中山医院心脏中心的苏茂龙。
血管紧张素II(Angiotensin II, AngII)能够诱导小鼠心肌肥大。当小鼠缺失TR3基因后，即使AngII持续给药4周，它们都不会有明显的心肌肥大迹象和相关的病理变化，心功能也表现正常。但是在野生型小鼠中，AngII持续给药4周后，小鼠出现心肌肥大以及相应的病理特征。进一步在左心室特异性敲低TR3基因后，在AngII诱导的心肌肥大模型中也可以看到敲低TR3后的大鼠明显能够抵抗AngII诱导的心肌肥大。这些结果提示TR3正向调控心肌肥大的发展过程。进一步在小鼠心肌肥大的标本中，我们发现了心肌细胞体积明显增大，并且是通过TR3的介导调控mTOR信号通路。机理分析表明，TR3与TSC1/TSC2复合物（mTOR抑制因子）结合，通过募集泛素分子结合TSC2，从而特异地降解TSC2蛋白，提高了mTOR活性。一旦mTOR活性提高，将对细胞体积的增大产生正调控。这一信号通路涉及的关键分子的表达水平在临床心肌肥大病例中得到了进一步的证实。因此，该研究第一次发现核受体TR3参与心肌肥大病理过程的调控，并阐明了其作用机制及信号调控通路，为临床心血管的预防和治疗提供了一个直接的和重要的靶点。（生物谷Bioon.com）
doi: 10.1002/emmm.201201369
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The orphan receptor TR3 participates in angiotensin II-induced cardiac hypertrophy by controlling mTOR signalling
Wang RH, He JP, Su ML, Luo J, Xu M, Du XD, Chen HZ, Wang WJ, Wang Y, Zhang N, Zhao BX, Zhao WX, Shan ZG, Han J, Chang C, Wu Q.
Angiotensin II (AngII) induces cardiac hypertrophy and increases the expression of TR3. To determine whether TR3 is involved in the regulation of the pathological cardiac hypertrophy induced by AngII, we established mouse and rat hypertrophy models using chronic AngII administration. Our results reveal that a deficiency of TR3 in mice or the knockdown of TR3 in the left ventricle of rats attenuated AngII-induced cardiac hypertrophy compared with the respective controls. A mechanistic analysis demonstrates that the TR3-mediated activation of mTORC1 is associated with AngII-induced cardiac hypertrophy. TR3 was shown to form a trimer with the TSC1/TSC2 complex that specifically promoted TSC2 degradation via a proteasome/ubiquitination pathway. As a result, mTORC1, but not mTORC2, was activated; this was accompanied by increased protein synthesis, enhanced production of reactive oxygen species and enlarged cell size, thereby resulting in cardiac hypertrophy. This study demonstrates that TR3 positively regulates cardiac hypertrophy by influencing the effect of AngII on the mTOR pathway. The elimination or reduction of TR3 may reduce cardiac hypertrophy; therefore, TR3 is a potential target for clinical therapy.
