Nrf2 participates in the protective effect of exogenous mitochondria against mitochondrial dysfunction in myocardial ischaemic and hypoxic injury
Nrf2 participates in the protective effect of exogenous mitochondria against mitochondrial dysfunction in myocardial ischaemic and hypoxic injury
复制标题
Nrf2参与外源性线粒体对心肌缺血缺氧损伤中线粒体功能障碍的保护作用
DOI：
10.1016/j.cellsig.2022.110266
复制
发表时间：
2022-01-31
影响因子：
4.8
通讯作者：
Wu, Naishi
中科院分区：
文献类型：
--
作者：
Jia, Liqun;Yang, Ling;Wu, Naishi
目的：冠心病是世界范围内主要的死亡原因之一。包括冠状动脉介入在内的治疗会导致并发症，如心肌缺血再灌注损伤(MIRI)。线粒体损伤或功能障碍是MIRI的重要病理基础。线粒体移植被认为是一种很有前途的心脏相关疾病的治疗策略，但其机制仍不清楚。NRF2在支持线粒体结构和功能完整性方面发挥着重要作用。本研究旨在探讨Nrf2在线粒体移植治疗MIRI中的作用。采用H9C2细胞缺氧/复氧(H/R)模型和野生型和Nrf2-/-小鼠左冠状动脉结扎诱导的MIRI模型，分别在体外和体内研究其机制。从健康H9C2细胞和胸大肌提取外源线粒体，分别作用于H9C2细胞和MIRI小鼠。检测线粒体内化、H9C2细胞损伤或凋亡、心肌损伤/功能、线粒体功能、形态、线粒体动力学和Nrf2途径各组成部分的表达。我们发现外源线粒体内化到H9C2心肌细胞中。外源性线粒体移植可减轻心肌细胞损伤、心肌细胞凋亡和线粒体功能障碍。外源性线粒体移植增加了Nrf2及其下游靶点的表达，减轻了心肌细胞损伤、心功能障碍、细胞凋亡、线粒体功能障碍以及线粒体融合和分裂失衡，并改善了野生型小鼠MIRI后的有丝分裂吞噬功能，但对Nrf2-/-小鼠没有影响。这些结果表明，外源性线粒体可以内化到心肌细胞并激活Nrf2途径，外源性线粒体通过Nrf2途径改善心功能，改善线粒体功能障碍。
Objective: Coronary artery disease is one of the leading causes of death worldwide. Treatments including coronary artery intervention can cause complications, such as myocardial ischaemia-reperfusion injury (MIRI). Mitochondrial injury or dysfunction is a key pathology of MIRI. Mitochondrial transplantation is considered a promising therapeutic strategy for cardiac-related diseases, but its mechanism is still unclear. Nrf2 is a prominent player in supporting the structural and functional integrity of mitochondria. In our research, we focused on the effect of Nrf2 in the treatment of MIRI by mitochondrial transplantation. H9C2 cells were subjected to hypoxia/ reoxygenation (H/R) and MIRI was induced in wild-type and Nrf2-/-mice by surgical ligation of the left coronary artery to elucidate the mechanism in vitro and in vivo, respectively. Exogenous mitochondria were extracted from healthy H9C2 cells and the pectoralis major and administered to H9C2 cells and mice with MIRI, respectively. Mitochondrial internalization, H9C2 cell injury or apoptosis, cardiac injury/function, mitochondrial function, morphology, mitochondrial dynamics, and the expression of components of the Nrf2 pathway were assessed. We found that exogenous mitochondria were internalized into H9C2 cardiomyocytes. Exogenous mitochondrial transplantation attenuated cardiomyocyte injury, cardiomyocyte apoptosis, and mitochondrial dysfunction. Exogenous mitochondrial transplantation increased the expression of Nrf2 and its downstream targets, attenuated cardiomyocyte injury, cardiac dysfunction, apoptosis, mitochondrial dysfunction, and mitochondrial fusion and fission imbalance, and improved mitophagy after MIRI in wild-type mice but not in Nrf2-/ -mice. These results suggested that exogenous mitochondria can be internalized into cardiomyocytes and activate the Nrf2 pathway and that exogenous mitochondria improve cardiac function and ameliorate mitochondrial dysfunction via the Nrf2 pathway.