Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein.
Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein.
复制标题
通过 hsp70 相互作用蛋白羧基末端的心脏特异性表达来预防阿霉素诱导的小鼠心肌功能障碍
DOI：
10.1038/srep28399
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发表时间：
2016-06-21
影响因子：
4.6
通讯作者：
Li HH
中科院分区：
文献类型：
--
作者：
Wang L;Zhang TP;Zhang Y;Bi HL;Guan XM;Wang HX;Wang X;Du J;Xia YL;Li HH
热休克蛋白70羧基端相互作用蛋白（CHIP）是一种重要的泛素连接酶/辅伴侣，在减轻心肌氧化应激、炎症反应、心肌细胞凋亡和自噬等方面发挥重要作用。心脏特异性CHIP转基因（CHIP-TG）小鼠和野生型（WT）同窝出生的小鼠用DOX或盐水处理。在CHIP-TG小鼠中，DOX诱导的心脏萎缩、功能障碍、炎症、氧化应激和心肌细胞凋亡显著减弱。在给予DOX 10天后，CHIP-TG小鼠也显示出比WT小鼠更高的存活率（40%对10%）。相反，在体外用siRNA敲低CHIP进一步增强了DOX诱导的心脏毒性作用。全基因芯片分析显示，DOX处理后，WT和CHIP-TG小鼠的差异表达基因主要涉及细胞凋亡、萎缩、免疫/炎症和氧化应激。从机制上讲，CHIP直接促进泛素介导的p53和SHP-1降解，这导致ERK 1/2和STAT 3通路的激活，从而改善DOX诱导的心脏毒性。
Carboxyl terminus of Hsp70-interacting protein (CHIP) is a critical ubiquitin ligase/cochaperone to reduce cardiac oxidative stress, inflammation, cardiomyocyte apoptosis and autophage etc. However, it is unclear whether overexpression of CHIP in the heart would exert protective effects against DOX-induced cardiomyopathy. Cardiac-specific CHIP transgenic (CHIP-TG) mice and the wild-type (WT) littermates were treated with DOX or saline. DOX-induced cardiac atrophy, dysfunction, inflammation, oxidative stress and cardiomyocyte apoptosis were significantly attenuated in CHIP-TG mice. CHIP-TG mice also showed higher survival rate than that of WT mice (40% versus 10%) after 10-day administration of DOX. In contrast, knockdown of CHIP by siRNAin vitrofurther enhanced DOX-induced cardiotoxic effects. Global gene microarray assay revealed that after DOX-treatment, differentially expressed genes between WT and CHIP-TG mice were mainly involved in apoptosis, atrophy, immune/inflammation and oxidative stress. Mechanistically, CHIP directly promotes ubiquitin-mediated degradation of p53 and SHP-1, which results in activation of ERK1/2 and STAT3 pathways thereby ameliorating DOX-induced cardiac toxicity.