Mitochondrial calcium uniporter inhibition provides cardioprotection in pressure overload-induced heart failure through autophagy enhancement.
Mitochondrial calcium uniporter inhibition provides cardioprotection in pressure overload-induced heart failure through autophagy enhancement.
复制标题
线粒体钙单向转运体抑制通过增强自噬在压力超负荷诱导的心力衰竭中提供心脏保护。
DOI：
10.1016/j.ijcard.2018.05.054
复制
发表时间：
2018-11
影响因子：
3.5
通讯作者：
Ziqing Yu;Ruizhen Chen;Ming-hui Li;Yong Yu;Yixiu Liang;Fei Han;Shengmei Qin;Xueying Chen;Yangang Su;J. Ge
中科院分区：
文献类型：
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作者：
Ziqing Yu;Ruizhen Chen;Ming-hui Li;Yong Yu;Yixiu Liang;Fei Han;Shengmei Qin;Xueying Chen;Yangang Su;J. Ge
背景心力衰竭的疾病负担很高，已知的心力衰竭治疗方法的效果并不令人满意。因此，寻找治疗心衰的新靶点具有重要意义。本研究旨在探讨线粒体钙单转运体(MCU)在超负荷心力衰竭(HF)中的作用及其与自噬的关系。方法与结果在压力超负荷心力衰竭的早期和晚期，MCU的表达均随着心脏增大、微管相关蛋白1A/1B轻链3B(LC3B)II/I比值和自噬小体含量的增加而上调，心功能受损和心室不同步。然而，隔离小体-1(SQSTM1/p62)水平下降，表明自噬通量受阻。MCU抑制剂Ru红治疗7周可改善心功能，减轻心功能病理改变。MCU抑制维持了线粒体的完整性，增加了LC3B II/I比值，上调了Parkin和PINK1的表达，下调了SQSTM1/p62的表达。抑制MCU也可减轻心衰的异步性，这可能与Cx43上调有关。体外研究证实了对MCU的干预导致自噬和有丝分裂吞噬的增加。MCU抑制可部分预防异丙肾上腺素引起的细胞过度膨胀。结论MCU抑制通过自噬和丝裂原吞噬作用在压力超负荷所致心力衰竭中发挥重要作用，而对MCU的干预具有心脏保护作用。据我们所知，MCU在HF中的作用及其与自噬和有丝分裂吞噬的关系首次被揭示。此外，我们的研究表明，MCU抑制可作为心力衰竭的一种新的治疗概念。
BackgroundHF incurs high disease burden, and the effectiveness of known HF treatments is unsatisfactory. Therefore, seeking novel therapeutic target of HF is important. The present study aimed to investigate the role of the mitochondrial calcium uniporter (MCU) and its relationship with autophagy in overload-induced heart failure (HF).Methods and resultsIn both early-stage and end-stage of pressure overload-induced HF, MCU appeared up-regulated along with heart enlargement, increased microtubule-associated proteins 1A/1B light chain 3B (LC3B) II/I ratio and autophagosome content, damaged cardiac function, and ventricular asynchrony. However, sequestosome-1 (SQSTM1/p62) level decreased indicating blockaded autophagic flux. Seven-week administration of MCU inhibitor ruthenium red improved cardiac function and mitigated its pathological change. MCU inhibition maintained mitochondrial integrity, increased LC3B II/I ratio, up-regulated Parkin and Pink1, and down-regulated SQSTM1/p62. MCU inhibition also alleviated ventricular asynchrony of HF, and this might be related to connexin-43 up-regulation. In vitro study validated intervention on MCU leading to elevation of autophagy and mitophagy. MCU inhibition could partly prevent from excessive cellular enlargement induced by isoprenaline.ConclusionsIn summary, MCU inhibition played an important role in pressure overload-induced heart failure through autophagy and mitophagy enhancement, and intervention on MCU offered cardioprotective effects. To our knowledge, the role of MCU in HF and its relationship with autophagy and mitophagy are firstly disclosed. Moreover, our study suggests that MCU inhibition could be explored as a novel therapeutic concept in HF.