心血管疾病已經(jīng)成為威脅人類健康的殺手之一,，負(fù)荷性的心肌肥大最終將帶來(lái)一系列心血管疾病,。因此,，了解心肌肥大產(chǎn)生的分子機(jī)理及其信號(hào)轉(zhuǎn)導(dǎo)通路的調(diào)控,，有助于我們預(yù)防和治療心血管疾病,。作為核受體,，TR3在細(xì)胞凋亡和血糖調(diào)控中發(fā)揮著重要作用,，但是，TR3是否參與心肌細(xì)胞肥大的調(diào)控還沒(méi)有任何報(bào)道,。
最近,，吳喬課題組通過(guò)動(dòng)物實(shí)驗(yàn)?zāi)Ｐ汀⒎肿蛹?xì)胞生物學(xué)實(shí)驗(yàn)和臨床病例分析,，證實(shí)了TR3通過(guò)調(diào)控mTOR信號(hào)通路影響心肌細(xì)胞大小,，結(jié)果導(dǎo)致心肌細(xì)胞肥大。該研究成果發(fā)表在國(guó)際SCI刊物EMBO Molecular Medicine（SCI影響因子：10.333）,。第一作者為廈門(mén)大學(xué)生科院的王榮浩,、何建平、羅杰以及中山醫(yī)院心臟中心的蘇茂龍,。
血管緊張素II(Angiotensin II, AngII)能夠誘導(dǎo)小鼠心肌肥大,。當(dāng)小鼠缺失TR3基因后，即使AngII持續(xù)給藥4周,，它們都不會(huì)有明顯的心肌肥大跡象和相關(guān)的病理變化,，心功能也表現(xiàn)正常。但是在野生型小鼠中,，AngII持續(xù)給藥4周后,，小鼠出現(xiàn)心肌肥大以及相應(yīng)的病理特征。進(jìn)一步在左心室特異性敲低TR3基因后,，在AngII誘導(dǎo)的心肌肥大模型中也可以看到敲低TR3后的大鼠明顯能夠抵抗AngII誘導(dǎo)的心肌肥大,。這些結(jié)果提示TR3正向調(diào)控心肌肥大的發(fā)展過(guò)程。進(jìn)一步在小鼠心肌肥大的標(biāo)本中,，我們發(fā)現(xiàn)了心肌細(xì)胞體積明顯增大,，并且是通過(guò)TR3的介導(dǎo)調(diào)控mTOR信號(hào)通路。機(jī)理分析表明,，TR3與TSC1/TSC2復(fù)合物（mTOR抑制因子）結(jié)合,，通過(guò)募集泛素分子結(jié)合TSC2，從而特異地降解TSC2蛋白,，提高了mTOR活性,。一旦mTOR活性提高，將對(duì)細(xì)胞體積的增大產(chǎn)生正調(diào)控,。這一信號(hào)通路涉及的關(guān)鍵分子的表達(dá)水平在臨床心肌肥大病例中得到了進(jìn)一步的證實(shí),。因此，該研究第一次發(fā)現(xiàn)核受體TR3參與心肌肥大病理過(guò)程的調(diào)控,，并闡明了其作用機(jī)制及信號(hào)調(diào)控通路,，為臨床心血管的預(yù)防和治療提供了一個(gè)直接的和重要的靶點(diǎn)。（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
Rong-Hao Wang, Jian-Ping He, Mao-Long Su, Jie Luo, Ming Xu, Xiao-Dan Du, Hang-Zi Chen, Wei-Jia Wang, Yuan Wang, Nan Zhang, Bi-Xing Zhao, Wen-Xiu Zhao, Zhong-Gui Shan, Jiahuai Han, Chawnshang Chang, Qiao Wu
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
