A mechanism investigation on the effective strategy for alleviating acute myocardial infarction associated with sleep deprivation

Acute myocardial infarction (AMI) and insomnia are mutually causal. However, therapeutic strategies for AMI combined with insomnia remain limited. Mechanistically, parachlorophenylalanine (PCPA)-induced sleep deprivation (SD) exacerbates AMI by activating the sympathetic nervous system and triggering systemic inflammatory responses. However, the specific cascade through which PCPA-induced SD-mediated systemic inflammation aggravates myocardial injury remains unclear. Bisoprolol amlodipine tablet (BAT), containing bisoprolol and amlodipine, exerts cardiovascular protective effects, in which bisoprolol mitigates sympathetic overactivation, while amlodipine alleviates AMI-related inflammatory responses. Shumian capsule (SMC) improves sleep quality with potential anti-inflammatory and neuroprotective properties. Given the complementary mechanisms of BAT and SMC, and the unmet clinical need for safe, effective therapies targeting AMI-insomnia comorbidity, this study aims to explore the therapeutic mechanisms of BAT combined with SMC on myocardial injury induced by AMI and PCPA-induced SD, providing novel insights for clinical practice. Male Sprague Dawley rats were randomly divided into five groups: sham, MI, MI + SD, BAT, and BAT + SMC. The MI model was established by ligating the left anterior descending coronary artery, and the SD model was induced by intraperitoneal injection of parachlorophenylalanine. After model establishment, rats in the BAT group received BAT (1.05 mg/kg, i.g.), and those in the BAT + SMC group received BAT combined with SMC (252 mg/kg, i.g.) for one week. Behavioral tests, echocardiography, heart rate, heart weight (HW)/body weight (BW), HW/tibia length (TL), histopathological staining, immunofluorescence co-localization, ELISA, qRT-PCR, and Western blot were used to evaluate anxiety- and depression-like behaviors, cardiac function, tissue injuries, inflammatory responses, and related gene and protein expression. PCPA-induced SD mediated the aggravation of MI-induced anxiety and depression-like behaviors, hippocampal and myocardial pathological injuries, myocardial fibrosis, apoptosis, and cardiac dysfunction in rats. It also increased the levels of myocardial injury biomarkers and inflammatory cytokines, and was accompanied by elevated activation status of the Panx1/P2X7 pathway, which may correlate with promoted neutrophil recruitment and changes in NETosis-related markers. Compared with monotherapy with BAT, the BAT combined with the SMC group showed more favorable alterations across all measured parameters. Compared with monotherapy with BAT, the combination of BAT and SMC showed more favorable alterations in all measured parameters. BAT combined with SMC improved the sucrose preference index and locomotor activity, ameliorated neuronal and dendritic injuries in the hippocampus, increased left ventricular ejection fraction and shortening fraction, reduced left ventricular end-diastolic and end-systolic diameters, HR, HW/BW, and HW/TL, alleviated myocardial fibrosis and apoptosis, decreased the levels of CK-MB, cTnI, TNF-α, and IL-1β, was correlated with suppressed expression of Panx1 and P2X7, and presented lower levels of NETosis-related markers (MPO, NE, and Cit-H3). BAT combined with SMC may alleviate myocardial injuries in rats with AMI and PCPA-induced SD via alterations to the Panx1/P2X7 pathway-associated changes in NETosis-related markers. This combined intervention integrates the cardiovascular-protective actions of BAT with the sleep-improving and neuroprotective properties of SMC, which may help relieve the vicious cycle of PCPA-induced SD-triggered inflammation and myocardial damage. Our findings reveal a molecular link between the Panx1/P2X7-associated changes in NETosis-related markers and the therapeutic benefits of BAT and SMC combination therapy, and provide preclinical evidence for its potential translation into clinical practice. This innovative treatment strategy offers a safe and effective alternative for managing AMI patients with concurrent insomnia, addressing a critical unmet medical need.