Neuromodulation and Copper Chelation Reverse Sleep Fragmentation-Aggravated Myocardial Ischemia-Reperfusion Injury by Targeting NET-Induced Endothelial Cuproptosis

  • Research (Wash D C). 2026 May 8:9:1266. doi: 10.34133/research.1266.
Pilong Shi  1  2  3 ,  Yuetong Sha  1  3 ,  Xue Guan  4 ,  Jiawei Wu  5 ,  Jing Yang  1 ,  Dongyu Min  2 ,  Cong Wang  6 ,  Yonggang Cao  1 ,  Xinran Wang  1 ,  Yuandong Qiao  5  7  8 ,  Hongli Sun  1  3
Affiliations
  • 1. Department of Pharmacology, Harbin Medical University, Heilongjiang 163319, China.
  • 2. Experimental Center of Traditional Chinese Medicine, the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Liaoning 110000, China.
  • 3. Key Laboratory of Basic Research and Health Management on Chronic Diseases in Heilongjiang Province, Harbin Medical University, Heilongjiang 163319, China.
  • 4. Department of Medical Morphology, Harbin Medical University, Heilongjiang 163319, China.
  • 5. Key Laboratory of Frigid Zone Exercise Health Research and Translation in Heilongjiang Province, Harbin Medical University, Heilongjiang 163319, China.
  • 6. Department of Cardiology, Daqing People's Hospital, Heilongjiang 163319, China.
  • 7. Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Heilongjiang 150081, China.
  • 8. Department of Medical Genetics, Harbin Medical University, Heilongjiang 150081, China.
PMID: 42109881 DOI: 10.34133/research.1266
Abstract

This study sought to investigate the link between sleep disorders and cardiac microvascular injury in myocardial ischemia-reperfusion injury (MI/RI) mice. Mice were subjected to a sleep deprivation protocol within a designated chamber. During the light phase (ZT0 to ZT12), a sweep bar moved across the cage floor at 2-min intervals, whereas it remained static throughout the dark phase (ZT12 to ZT24), with this routine maintained for 16 weeks. Subsequently, an MI/RI model was established to assess the extent of cardiac microvascular injury, and the underlying mechanisms were explored via proteomic analyses. It was demonstrated that 16 weeks of sleep fragmentation (SF) intensified cardiac microvascular damage in MI/RI mice. From a mechanistic perspective, SF was found to induce sympathetic hyperactivity, elevate plasma epinephrine levels, and consequently facilitate neutrophil chemotaxis and the generation of neutrophil extracellular traps (NETs). Moreover, the findings revealed that NETs suppressed Atox1 expression, impaired ATP7A-mediated copper transport, and contributed to copper accumulation within cardiac microvascular endothelial cells (CMECs) and oxidative stress. This copper overload further augmented Cuproptosis, while these pathological alterations were shown to be reversible through sympathetic denervation, vagal electrical stimulation (ES), targeted delivery of copper chelators, or the inhibition of NETs. Overall, our data established that SF exacerbated MI/RI by promoting copper overload in CMECs. This study elucidated a molecular pathway through which sleep disturbances aggravated cardiac microvascular damage and suggested prospective targets for treatment strategies.

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