Sleep fragmentation exacerbates myocardial ischemia-reperfusion injury via hypothalamic paraventricular nucleus-resident OX1R-mediated sympathetic hyperactivity in adult mice

Sleep fragmentation (SF) is a prevalent sleep disorder with an increased risk of cardiovascular diseases. Although epidemiological studies have shown a strong link between SF and adverse cardiac outcomes, specific central neural mechanisms through which SF exacerbates myocardial ischemia-reperfusion injury (MI/RI) are unclear. This study investigated the role of orexin receptor 1 (OX1R) in the hypothalamic paraventricular nucleus (PVN) in SF-induced aggravation of MI/RI and the underlying mechanism using a mouse model. C57BL/6 mice were subjected to chronic SF for 16 weeks before MI/RI modeling. Cardiac function was assessed by echocardiography. Sympathetic activity was evaluated based on the heart rate variability analysis. Molecular changes were evaluated by western blotting, qRT-PCR, and immunohistochemistry. The in vivo functional role of OX1R signaling was determined by administering OX1R-specific antagonist SB-334867 via stereotaxic injection into the PVN in the experimental groups of mice. SF mice exhibited significantly worse cardiac dysfunction and larger infarct areas following MI/RI compared to the controls. This was accompanied by enhanced sympathetic nerve activity and elevated catecholamine levels. Specifically, SF upregulated OX1R expression in the PVN and increased the levels of neuronal activation markers such as c-Fos. Pharmacological blockade of OX1R in the PVN significantly ameliorated SF-induced cardiac dysfunction, reduced the infarct size, and suppressed sympathetic hyperactivity post-MI/RI. SF may aggravate MI/RI through PVN OX1R-associated sympathetic hyperactivation. Pharmacological inhibition of OX1R improved cardiac outcomes, supporting the involvement of the PVN OX1R-sympathetic pathway in sleep disruption related cardiac injury. SF exacerbates MI/RI by upregulating OX1R in the hypothalamic paraventricular nucleus, leading to sympathetic hyperactivity and worsened cardiac outcomes.Selective blockade of OX1R in the hypothalamic paraventricular nucleus effectively attenuates SF–induced sympathetic overactivation and myocardial injury.Our findings implicate the PVN OX1R-sympathetic axis in the pathogenesis of SF-induced cardiac injury, providing a basis for future mechanistic research. SF exacerbates MI/RI by upregulating OX1R in the hypothalamic paraventricular nucleus, leading to sympathetic hyperactivity and worsened cardiac outcomes. Selective blockade of OX1R in the hypothalamic paraventricular nucleus effectively attenuates SF–induced sympathetic overactivation and myocardial injury. Our findings implicate the PVN OX1R-sympathetic axis in the pathogenesis of SF-induced cardiac injury, providing a basis for future mechanistic research.

睡眠碎片化（Sleep fragmentation, SF）是一种高发睡眠障碍，可增加心血管疾病的患病风险。尽管流行病学研究已证实SF与不良心脏结局存在密切关联，但SF加重心肌缺血再灌注损伤（myocardial ischemia-reperfusion injury, MI/RI）的特异性中枢神经机制仍未明确。本研究借助小鼠模型，探讨下丘脑室旁核（hypothalamic paraventricular nucleus, PVN）内食欲素受体1（orexin receptor 1, OX1R）在SF诱导的MI/RI加重效应中的作用及潜在机制。

将C57BL/6小鼠进行16周慢性SF造模，随后实施MI/RI造模。通过超声心动图评估心功能，采用心率变异性分析评价交感神经活性，借助蛋白质免疫印迹、实时定量聚合酶链反应（qRT-PCR）及免疫组织化学技术检测分子水平改变。向实验组小鼠的PVN内立体定位注射OX1R特异性拮抗剂SB-334867，以此明确OX1R信号通路的在体功能作用。

与对照组相比，SF组小鼠在MI/RI造模后心功能障碍程度显著加重，梗死面积更大，同时伴随交感神经活性增强与儿茶酚胺水平升高。具体而言，SF可上调PVN内OX1R的表达，并升高c-Fos等神经元活化标志物的水平。对PVN内的OX1R实施药理学阻断，可显著改善SF诱导的心功能障碍，缩小梗死体积，并抑制MI/RI术后的交感过度激活。

SF可能通过PVN OX1R相关的交感过度激活加重MI/RI。对OX1R进行药理学抑制可改善心脏结局，证实PVN OX1R-交感通路参与睡眠紊乱相关心脏损伤。SF通过上调下丘脑室旁核内的OX1R表达加重MI/RI，进而引发交感过度激活与不良心脏结局。选择性阻断下丘脑室旁核内的OX1R，可有效缓解SF诱导的交感过度激活与心肌损伤。本研究结果表明，PVN OX1R-交感轴参与SF诱导心脏损伤的发病过程，为后续机制研究提供了理论依据。

SF通过上调下丘脑室旁核内的OX1R表达加重MI/RI，进而引发交感过度激活与不良心脏结局。选择性阻断下丘脑室旁核内的OX1R，可有效缓解SF诱导的交感过度激活与心肌损伤。本研究结果表明，PVN OX1R-交感轴参与SF诱导心脏损伤的发病过程，为后续机制研究提供了理论依据。