The alteration of protein prenylation induces cardiomyocyte hypertrophy through Rheb-mTORC1 signalling and leads to chronic heart failure
The alteration of protein prenylation induces cardiomyocyte hypertrophy through Rheb-mTORC1 signalling and leads to chronic heart failure
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DOI：
10.1002/path.4480
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发表时间：
2015-04-01
影响因子：
7.3
通讯作者：
Li, Chao-Jun
中科院分区：
文献类型：
--
作者：
Xu, Na;Guan, Shan;Li, Chao-Jun
G蛋白调节的细胞功能对心肌细胞至关重要，其基因表达或蛋白质修饰的任何失调都可能导致病理性心脏肥大。在此，我们报告说，蛋白质异戊二烯化，一种促进G蛋白与细胞膜结合的蛋白质修饰，可能控制心肌细胞肥大的过程。我们发现，牛儿基牛儿基二磷酸合酶（GGPPS），一个关键酶参与蛋白质异戊二烯化，发挥了关键作用，在出生后的心脏生长，通过调节心肌细胞的大小。心脏特异性敲除小鼠GGPPS导致自发性心脏肥大，从第4周开始，伴随着心肌细胞的持续增大。这种肥大效应是通过改变G蛋白的异戊烯化而发生的。异戊二烯化，膜缔合和疏水性的评估表明，Rheb是超活化的，并增加mTORC 1信号通路后GGPPS删除。蛋白法尼基化或mTORC 1抑制阻断GGPPS敲低诱导的mTORC 1激活，并抑制较大的新生大鼠心室肌细胞大小和心肌细胞肥大，证明了FPP-Rheb-mTORC 1轴在GGPPS缺乏诱导的心肌细胞肥大中的核心作用。持续的心肌细胞肥大逐渐引起心脏代偿失调和功能障碍，最终导致心力衰竭和成人死亡。重要的是，GGPPS在经受横向主动脉缩窄（TAC）的小鼠的肥大心脏和衰竭的人类心脏中下调。HPLC-MS/MS检测显示，压力超负荷后心肌组织中FPP：GGPP比值增加。结论：蛋白质异戊烯化改变促进心肌细胞肥大生长，可能是心力衰竭发病机制的一个潜在原因，并可能为肥厚性心脏病的临床治疗提供新的分子靶点。版权所有（c）2014大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
G protein-regulated cell function is crucial for cardiomyocytes, and any deregulation of its gene expression or protein modification can lead to pathological cardiac hypertrophy. Herein, we report that protein prenylation, a lipidic modification of G proteins that facilitates their association with the cell membrane, might control the process of cardiomyocyte hypertrophy. We found that geranylgeranyl diphosphate synthase (GGPPS), a key enzyme involved in protein prenylation, played a critical role in postnatal heart growth by regulating cardiomyocyte size. Cardiac-specific knockout of GGPPS in mice led to spontaneous cardiac hypertrophy, beginning from week 4, accompanied by the persistent enlargement of cardiomyocytes. This hypertrophic effect occurred by altered prenylation of G proteins. Evaluation of the prenylation, membrane association and hydrophobicity showed that Rheb was hyperactivated and increased mTORC1 signalling pathway after GGPPS deletion. Protein farnesylation or mTORC1 inhibition blocked GGPPS knockdown-induced mTORC1 activation and suppressed the larger neonatal rat ventricle myocyte size and cardiomyocyte hypertrophy in vivo, demonstrating a central role of the FPP-Rheb-mTORC1 axis for GGPPS deficiency-induced cardiomyocyte hypertrophy. The sustained cardiomyocyte hypertrophy progressively provoked cardiac decompensation and dysfunction, ultimately causing heart failure and adult death. Importantly, GGPPS was down-regulated in the hypertrophic hearts of mice subjected to transverse aortic constriction (TAC) and in failing human hearts. Moreover, HPLC-MS/MS detection revealed that the myocardial farnesyl diphosphate (FPP):geranylgeranyl diphosphate (GGPP) ratio was enhanced after pressure overload. Our observations conclude that the alteration of protein prenylation promotes cardiomyocyte hypertrophic growth, which acts as a potential cause for pathogenesis of heart failure and may provide a new molecular target for hypertrophic heart disease clinical therapy. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.