FAT10 protects cardiac myocytes against apoptosis.
FAT10 protects cardiac myocytes against apoptosis.
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DOI：
10.1016/j.yjmcc.2013.01.018
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发表时间：
2013-06
影响因子：
5
通讯作者：
Hong, Kui
中科院分区：
文献类型：
--
作者：
Peng, Xiaogang;Shao, Jianghua;Shen, Yang;Zhou, Yunguo;Cao, Qing;Hu, Jinzhu;He, Wenfeng;Yu, Xin;Liu, Xiuxia;Marian, Ali J.;Hong, Kui
FAT 10是泛素样蛋白家族的新成员，在心脏中的生物学功能尚未确定。我们的目标是确定FAT 10在心脏中的作用。FAT 10在正常人和鼠心脏中表达，如通过qPCR和蛋白质印迹检测的。FAT 10在心肌梗死边缘区的心脏和缺氧/复氧（H/R）应激的培养的新生大鼠心肌细胞（NRCM）中的表达增加。慢病毒介导的FAT 10在NRCM中的过表达降低了p53（TP 53）及其靶miR-34 a的水平，而BCL 2水平（miR-34 a的靶）增加，BAX水平（促凋亡蛋白）降低。这些变化与细胞凋亡减少有关，通过对膜联蛋白-V表达的FACS分析和TUNEL测定检测到，响应于H/R损伤。通过shRNA靶向敲低FAT 10具有相反的效果。同样，慢病毒介导的miR-34 a表达与NRCM中BCL-2水平降低和BAX水平增加相关，并且还逆转了在FAT 10过表达时观察到的BCL-2和BAX水平的变化。用蛋白酶体抑制剂MG 132治疗NRCM增加了p53和miR-34 a水平，降低了BLC 2/BAX比率。这些变化在FAT 10过表达时没有逆转。因此，FAT 10在心脏和NRCM中响应于H/R应激而上调，其保护心肌细胞免于凋亡。FAT 10的抗凋亡作用与抑制p53相关，可能通过脂肪化和蛋白酶体降解，减少miR-34 a表达，以及BCL 2/BAX蛋白的抗凋亡转变。因此，FAT 10是一种心脏保护蛋白。
FAT10 is a new member of the ubiquitin-like protein family with yet-to-be defined biological functions in the heart. Our objective was to determine the role of FAT10 in the heart. FAT10 is expressed in the normal human and murine hearts, as detected by qPCR and Western blotting. Expression of FAT10 is increased in the heart at the border zone of myocardial infarction and in cultured neonatal rat cardiac myocytes (NRCM) subjected to hypoxia/reoxygenation (H/R) stress. Lentiviral-mediated overexpression of FAT10 in NRCM reduced p53 (TP53) and its target miR-34a levels, while BCL2 level, a target of miR-34a, was increased and BAX level, a pro-apoptotic protein, was reduced. These changes were associated with reduced apoptosis, detected by FACS analysis of annexin-V expression and TUNEL assay, in response to H/R injury. Knock down of FAT10 by shRNA targeting had the opposite effects. Likewise, lentiviral mediated expression of miR-34a was associated with reduced BCL2 and increased BAX levels in NRCM and also reversed changes in BCL-2 and BAX levels observed upon over-expression of FAT10. Treatment of NRCM with proteasome inhibitor MG132 increased p53 and miR-34a levels and reduced BLC2/BAX ratio. These changes were not reversed upon over-expression of FAT10. Thus, FAT10 is upregulated in the heart and NRCM in response to H/R stress, which protects cardiac myocytes against apoptosis. The anti-apoptotic effects of FAT10 are associated with suppression of p53, probably through fatylation and proteasomal degradation, reduced miR-34a expression, and a shift in the BCL2/BAX proteins against apoptosis. Thus, FAT10 is a cardioprotective protein.
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