Yin Ran, Wang Huan, Li Chun, Wang Lulu, Lai Songqing, Yang Xianhe, Hong Daojun, Zhang Wan
Department of Cardiology, The First Affiliated Hospital of Nanchang University, 330006, Nanchang, Jiangxi, P. R. China.
Department of Neurology, The First Affiliated Hospital of Nanchang University, 330006, Nanchang, Jiangxi, P. R. China.
Cell Death Discov. 2022 Feb 21;8(1):75. doi: 10.1038/s41420-022-00870-4.
High levels of homocysteine (Hcy) associated with cardiovascular events are accompanied by increased copper (Cu) concentrations in the blood. Hcy has been shown to promote endothelial dysfunction, whereas the effect of Hcy on cardiomyocytes and the role of Cu in the pathogenesis remain less understood. In the present study, it is demonstrated that the combination of Hcy and Cu-induced apoptosis and autosis of cardiomyocytes simultaneously, and thus led to cardiac dysfunction in hyperhomocysteinemic rats. These effects were associated with p22 activation and NADPH oxidase (NOX)-mediated p62 upregulation. Inhibition of the expression of p22 or p62 in cardiomyocytes significantly attenuated Hcy and Cu-mediated reactive oxygen species (ROS) generation and cell death. Furthermore, interrupting the NOX-p62 axis prevented diastolic dysfunction in hyperhomocysteinemic rats (HcyR). These findings establish that the induction of apoptosis and autosis of cardiomyocytes through stimulating the NOX-p62-signaling pathway constitutes a novel mechanism of Hcy and Cu-induced cardiac dysfunction.
与心血管事件相关的高同型半胱氨酸（Hcy）水平伴随着血液中铜（Cu）浓度的升高。已证明Hcy会促进内皮功能障碍，而Hcy对心肌细胞的影响以及Cu在发病机制中的作用仍了解较少。在本研究中，证明了Hcy和Cu的组合同时诱导心肌细胞凋亡和自噬，并因此导致高同型半胱氨酸血症大鼠心脏功能障碍。这些作用与p22激活和NADPH氧化酶（NOX）介导的p62上调有关。抑制心肌细胞中p22或p62的表达可显著减弱Hcy和Cu介导的活性氧（ROS）生成和细胞死亡。此外，中断NOX-p62轴可预防高同型半胱氨酸血症大鼠（HcyR）的舒张功能障碍。这些发现表明，通过刺激NOX-p62信号通路诱导心肌细胞凋亡和自噬构成了Hcy和Cu诱导心脏功能障碍的新机制。
