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.