The effects of Tel2 on cardiomyocyte survival.
The effects of Tel2 on cardiomyocyte survival.
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Tel2 对心肌细胞存活的影响。
DOI：
10.1016/j.lfs.2019.116665
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发表时间：
2019
期刊：
影响因子：
6.1
通讯作者：
Matsui,Takashi
中科院分区：
文献类型：
--
作者：
Yorichika,Naaiko;Baba,Yuichi;Shimada,BrianaK;Thakore,Manoj;Wong,SharonM;Kobayashi,Motoi;Higa,JasonK;Matsui,Takashi
rapamycin （mTOR）是PIKK（磷酸肌苷激酶相关激酶）家族的一员，其机制靶点的过度表达可以保护心肌细胞免受病理性刺激（如缺血）引起的细胞死亡。我们之前报道过mTOR的翻译后修饰在调节心脏mTOR表达中起重要作用。这项研究的目的是观察Tel2（端粒维持2），一种调节PIKKs丰度的蛋白质，是否具有与mTOR相似的心脏保护作用。Tel2在心肌细胞中没有很好的特征，因此我们研究了缺血应激条件下Tel2对心肌细胞活力的影响。材料与方法在HL-1心肌细胞中过表达Tel2或用siRNA沉默Tel2，探讨缺氧条件下Tel2过表达和下调对细胞存活的影响。用转染了Tel2腺病毒的成年小鼠心肌细胞检测Tel2是否能充分预防过氧化氢（H2O2）对心肌细胞的杀伤作用。关键发现：在HL-1细胞中，表达Tel2增加mTOR表达，同时mTOR复合物1 （mTORC1）和mTORC2活性增加。Tel2的缺失降低了mTOR的表达，也降低了mTORC1和mTORC2的活性。在HL-1细胞和成年小鼠心肌细胞中，Tel2过表达可保护缺血应激下的心肌细胞。这些作用依赖于mTOR，因为mTOR抑制剂减弱了Tel2的作用。虽然Tel2基因沉默不影响正常缺氧条件下的细胞存活，但在缺氧条件下，Tel2基因沉默使心肌细胞更容易死亡。调控Tel2表达增加mtor介导的心肌细胞存活，靶向Tel2可能是治疗缺血性心脏病的另一种治疗策略。
AimsOverexpression of the mechanistic target of rapamycin (mTOR), a member of the PIKK (phosphoinositide kinase-related kinase) family, protects cardiomyocytes from cell death induced by pathological stimuli such as ischemia. We previously reported that posttranslational modification of mTOR plays an important role in regulating cardiac mTOR expression. The aim of this study was to see if Tel2 (telomere maintenance 2), a protein that regulates the abundance of PIKKs, confers similar cardioprotective effects as mTOR. Tel2 is not well-characterized in cardiomyocytes, therefore we examined the effects of Tel2 on cardiomyocyte viability under ischemic stress conditions.Materials and methodsWe overexpressed Tel2 or silenced Tel2 with siRNA in the HL-1 cardiomyocyte cell line to survey the effects of Tel2 overexpression and downregulation on cell survival during hypoxia. Adult mouse cardiomyocytes transfected with Tel2 adenoviruses were used to test whether Tel2 sufficiently prevented cardiomyocyte cell death against hydrogen peroxide (H2O2).Key findingsOverexpressing Tel2 increased mTOR expression with a concomitant increase in mTOR Complex 1 (mTORC1) and mTORC2 activity in HL-1 cells. Tel2 deletion decreased mTOR expression, and mTORC1 and mTORC2 activity accordingly. In both HL-1 cells and adult mouse cardiomyocytes, Tel2 overexpression protected cardiomyocytes under ischemic stress. These effects were mTOR-dependent, as mTOR inhibitors blunted the effects of Tel2. While gene silencing of Tel2 did not affect cell survival under normoxia, Tel2 silencing made cardiomyocytes more vulnerable to cell death under hypoxia.SignificanceUpregulating Tel2 expression increases mTOR-mediated cardiomyocyte survival and targeting Tel2 could be another therapeutic strategy against ischemic heart disease.