High-mobility group box 1-mediated heat shock protein beta 1 expression attenuates mitochondrial dysfunction and apoptosis
High-mobility group box 1-mediated heat shock protein beta 1 expression attenuates mitochondrial dysfunction and apoptosis
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DOI：
10.1016/j.yjmcc.2015.02.018
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发表时间：
2015-05-01
影响因子：
5
通讯作者：
Kubota, Isao
中科院分区：
文献类型：
--
作者：
Narumi, Taro;Shishido, Tetsuro;Kubota, Isao
目的：心肌细胞的凋亡被认为是阿霉素心脏毒性的原因，因为它导致心肌组织丢失和收缩功能障碍。鉴于高迁移率族蛋白1(HMGB1)是一种能够抑制细胞凋亡的核DNA结合蛋白，我们旨在阐明HMGB1在阿霉素诱导的心肌病热休克蛋白β1(HSPB1)表达中的作用。方法和结果：与野生型(WT)小鼠相比，心脏特异性高表达HMGB1(HMGB1-TG)的小鼠心肌线粒体损伤、心肌细胞凋亡和心功能障碍明显减轻。HMGB1-TG小鼠注射阿霉素后HSPB1水平显著高于WT小鼠。HMGB1基因表达上调HSPB1在蛋白和mRNA水平的表达，HMGB1抑制阿霉素诱导的心肌细胞线粒体功能障碍和细胞凋亡。HSPB1沉默可阻断HMGB1对心肌细胞凋亡的抑制作用。阿霉素增加HMGB1与热休克因子2的结合，增强热休克元件启动子的活性。此外，HMGB1的过表达大大提高了热休克元件启动子的活性。沉默热休克因子2可减弱HMGB1依赖的HSPB1的表达，并降低HMGB1在阿霉素刺激后抑制caspase-3裂解积聚的能力。结论：我们首次在体内和体外报道了心脏HMGB1增加HSPB1的表达和减轻与阿霉素诱导的心肌病相关的心肌细胞凋亡的证据。心脏HMGB1以热休克因子2依赖的方式增加心肌细胞HSPB1的表达。(C)2015年提交人。爱思唯尔有限公司出版。
Aims: Apoptosis of cardiomyocytes is thought to account for doxorubicin cardiotoxicity as it contributes to loss of myocardial tissue and contractile dysfunction. Given that high-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein capable of inhibiting apoptosis, we aimed to clarify the role of HMGB1 in heat shock protein beta 1 (HSPB1) expression during doxorubicin-induced cardiomyopathy.Methods and results: Mitochondrial damage, cardiomyocyte apoptosis, and cardiac dysfunction after doxorubicin administration were significantly attenuated in mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) compared with wild type (WT) -mice. HSPB1 levels after doxorubicin administration were significantly higher in HMGB1-Tg mice than in WT mice. Transfection with HMGB1 increased the expression of HSPB1 at both the protein and mRNA levels, and HMGB1 inhibited mitochondrial dysfunction and apoptosis after exposure of cardiomyocytes to doxorubicin. HSPB1 silencing abrogated the inhibitory effect of HMGB1 on cardiomyocyte apoptosis. Doxorubicin increased the binding of HMGB1 to heat shock factor 2 and enhanced heat shock element promoter activity. Moreover, HMGB1 overexpression greatly enhanced heat shock element promoter activity. Silencing of heat shock factor 2 attenuated HMGB1-dependent HSPB1 expression and abrogated the ability of HMGB1 to suppress cleaved caspase-3 accumulation after doxorubicin stimulation.Conclusions: We report the first in vivo and in vitro evidence that cardiac HMGB1 increases HSPB1 expression and attenuates cardiomyocyte apoptosis associated with doxorubicin-induced cardiomyopathy. Cardiac HMGB1 increases HSPB1 expression in cardiomyocytes in a heat shock factor 2-dependent manner. (C) 2015 The Authors. Published by Elsevier Ltd.