Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China.
National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China.
Nat Commun. 2024 May 7;15(1):3834. doi: 10.1038/s41467-024-48227-y.
Sleep disorders increase the risk and mortality of heart disease, but the brain-heart interaction has not yet been fully elucidated. Cuproptosis is a copper-dependent type of cell death activated by the excessive accumulation of intracellular copper. Here, we showed that 16 weeks of sleep fragmentation (SF) resulted in elevated copper levels in the male mouse heart and exacerbated myocardial ischemia-reperfusion injury with increased myocardial cuproptosis and apoptosis. Mechanistically, we found that SF promotes sympathetic overactivity, increases the germination of myocardial sympathetic nerve terminals, and increases the level of norepinephrine in cardiac tissue, thereby inhibits VPS35 expression and leads to impaired ATP7A related copper transport and copper overload in cardiomyocytes. Copper overload further leads to exacerbated cuproptosis and apoptosis, and these effects can be rescued by excision of the sympathetic nerve or administration of copper chelating agent. Our study elucidates one of the molecular mechanisms by which sleep disorders aggravate myocardial injury and suggests possible targets for intervention.
睡眠障碍会增加患心脏病的风险和死亡率，但脑心相互作用尚未完全阐明。铜死亡是一种由细胞内铜积累过多引发的依赖铜的细胞死亡类型。在这里，我们发现 16 周的睡眠片段化（SF）导致雄性小鼠心脏内铜水平升高，并加剧了心肌缺血再灌注损伤，导致心肌铜死亡和凋亡增加。在机制上，我们发现 SF 促进交感神经活性增加，增加心肌交感神经末梢的发芽，并增加心脏组织去甲肾上腺素水平，从而抑制 VPS35 表达，导致心肌细胞中与 ATP7A 相关的铜转运和铜过载受损。铜过载进一步导致铜死亡和凋亡加剧，这些影响可以通过切除交感神经或给予铜螯合剂来挽救。我们的研究阐明了睡眠障碍加重心肌损伤的分子机制之一，并为干预提供了可能的靶点。
