Dataset Information

Sleep fragmentation exacerbates cardiac microvascular endothelial cell cuproptosis via promoting neutrophil extracellular trap formation in myocardial ischemia-reperfusion injury

ABSTRACT: Objective: This study aimed to investigate the relationship between sleep disorders and cardiac microvascular injury in myocardial ischemia-reperfusion injury (MI/RI) mice. Design: Mice were placed in a sleep deprivation chamber. The sweep bar moved along the bottom of the cage every 2 min during the light cycle (ZT0-12) and was stationary during the dark cycle (ZT12-24) for 16 weeks. Then, a MI/RI model was prepared to evaluate cardiac microvascular injury and investigate its specific mechanism via proteomics analysis. Results: Here, we showed that 16 weeks of sleep fragmentation (SF) exacerbated cardiac microvascular injury in MI/RI mice. Mechanistically, we found that SF promotes sympathetic overactivity, increases the level of norepinephrine (EPI) in plasma, thereby promotes the chemotaxis of neutrophils (NEs) and formation of Neutrophil extracellular traps (NETs). Furthermore, our data indicated that NETs inhibit Atox1 expression and leads to impaired ATP7A related copper transport and copper overload in cardiac microvascular endothelial cells (CMECs). Copper overload further leads to exacerbated cuproptosis, and these effects can be rescued by excision of the sympathetic nerve, targeted administration of copper chelating agent or NETs inhibitor. Conclusions: This study demonstrated that SF exacerbated MI/RI by promoting copper overload in CMECs. Our study elucidated one of the molecular mechanisms by which sleep disorders aggravate cardiac microvascular injury and suggested possible tar gets for intervention.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Hongli Sun

LAB HEAD: Hongli Sun

PROVIDER: PXD066510 | Pride | 2026-06-08

REPOSITORIES: Pride

ACCESS DATA

Publications

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

Shi Pilong P Sha Yuetong Y Guan Xue X Wu Jiawei J Yang Jing J Min Dongyu D Wang Cong C Cao Yonggang Y Wang Xinran X Qiao Yuandong Y Sun Hongli H

Research (Washington, D.C.) 20260508

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 ...[more]

PMID: 42109881

Similar Datasets

Project description:Background: Sustained sleep insufficiency impairs immune system and increases the adverse outcomes of cardiovascular diseases. However, the role and mechanisms prolonged sleep fragmentation (SF) on the outcomes of myocardial infarction (MI) remains elusive. Methods: Among 497 MI patients with complete sleep data participating in the National Health and Nutrition Examination Survey, the association between different types of sleep disorders and post-MI survivability was evaluated. We then developed a mouse model with 10 weeks of SF followed by MI surgery. Emergency hematopoiesis and neutrophil expansion were analyzed. Potential mechanisms were explored using bone marrow (BM) transplantation, anti-SiglecF neutralizing antibodies and Interferon alpha and beta receptor subunit 1 knockout (Ifnar1-/-) in BM. Results: Frequent nocturnal awakening independently predicted reduced survival rate of MI patients, with a hazard ratio (HR) of 2.136 (95% CI=1.142-3.995). Increased infarct size, deteriorated cardiac function and lower survival rate were also observed in MI mice pretreated with 10-week SF. SF facilitated post-MI neutrophil expansion and infiltration into infarct area, differentiating into SiglecFhi subset. Inhibition of SiglecFhi neutrophils allowed for the alleviations of post-MI cardiac remodeling. Furthermore, BM progenitors were skewed toward neutrophil lineage concomitant with the clonal expansion of granulocyte-monocyte progenitors (GMPs) in MI mice pretreated with 10-week SF. Transcriptome analysis and functional experiments revealed that activation of type I interferon (IFN) signaling was involved in this process, while depletion of Ifnar1 in BM and administration of IFNAR1-neutralizing antibodies significantly alleviated post-MI cardiac remodeling and neutrophil expansion. Conclusions: SF aggravates post-MI cardiac remodeling and dysfunction through promoting GMP differentiation and neutrophil expansion. Blockage of type I IFN could alleviate this detrimental influence.

Project description:The occurrence of cardiovascular diseases increases dramatically in postmenopausal aged women. Accumulating evidence has indicated that estrogen protects hearts from cardiovascular diseases. However, the underlying mechanisms was not fully elucidated. This present study was designed to investigate the function of GPR30 in pathological heart failure of aged female mice with the focus of neutrophil extracellular traps (NETs). Transverse aortic constriction (TAC) surgery was performed to induce heart failure in aged female mice. RNA-seq and flow cytometry were employed to study neutrophils activity during heart failure of aged female mice. Heart function and cardiac fibrosis as well as NETs level were assessed. Reduction of NETs by DNase I administration、 G1 treatment and Trex1 overexpression in macrophage were conducted to elucidate the role of NETs in this pathological process. Co-culture of RAW264.7 macrophages and neutrophils were used to examine the function of Trex1 in macrophage. Our bulk RNA-seq analysis showed that neutrophil migration and neutrophil chemotaxis were markedly enhanced at the early stage of pathological cardiac hypertrophy in aged female hearts. We further demonstrated that NETs generated by these activated neutrophils in aged female myocardium at the late stage were significantly increased following TAC surgery accompanied with the reduction of GPR30 expression. GPR30 agonist G1 treatment preserved cardiac function and reduced myocardial fibrosis in aged female mice with heart failure. To further validate the key role of NETs, DNase I administration markedly enhanced cardiac performance and attenuated cardiac fibrosis with the overall neutrophil reduction in the myocardium. Our in vitro results showed that overexpression of Trex1 in RAW264.1 macrophage enhanced neutrophil NETs clearance, thus indicating that GPR30 activation could increase the exonuclease three prime repair exonuclease 1 (Trex1) expression which may be associated with the reduction of NETs level in hypertrophied hearts. NETs generated by neutrophils exacerbate pressure overload–induced heart failure in aged female mice. GPR30 activates Trex1 signaling in macrophage to enhance NTEs degradation and thus attenuates TAC-induced cardiac dysfunction, providing an avenue for the novel therapeutics against cardiac dysfunction in postmenopausal women.

			Action	DRS
	C1.raw	Raw
	C3.raw	Raw
	C4.raw	Raw
	M1.raw	Raw
	M2.raw	Raw

Dataset Information

Sleep fragmentation exacerbates cardiac microvascular endothelial cell cuproptosis via promoting neutrophil extracellular trap formation in myocardial ischemia-reperfusion injury

Dataset's files

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets