APOM-associated inflammation and apoptosis in stroke-exacerbated myocardial infarction: implications for brain-heart interactions.

Stroke is a significant risk factor for myocardial infarction in clinical data analysis.

• Clinical data analysis yielded an odds ratio of 4.5 for MI risk associated with stroke.
• Acute ischemic stroke (AIS) was identified as a critical driver that exacerbates myocardial infarction within the brain-heart syndrome framework.
• The clinical correlation analysis was part of the study's initial evaluation before proceeding to animal models.

Middle cerebral artery occlusion (MCAO) significantly exacerbated post-MI electrocardiographic abnormalities and myocardial inflammatory responses in a combined mouse model.

• A combined mouse model of MCAO and MI was established to assess neurological and cardiac injury simultaneously.
• MCAO elevated circulating levels of cardiac troponin T (cTnT) and IL-1β compared to MI alone.
• Electrocardiographic abnormalities were significantly worsened in the combined MCAO+MI model relative to MI alone.

APOM was significantly downregulated in the heart, brain, and serum following stroke in both mouse models and AIS patients.

• Quantitative proteomics and Weighted Gene Co-expression Network Analysis (WGCNA) were used to screen key differentially expressed proteins.
• APOM downregulation was identified in heart, brain, and serum tissue compartments post-stroke in mice.
• The downregulation trend observed in mice was consistent with observations in AIS patients, supporting translational relevance.

APOM deficiency markedly worsened cardiac conduction disturbances, histological damage, and inflammatory responses in MI mice.

• APOM-knockout (KO) mice were used to validate the role of APOM in myocardial injury.
• APOM-KO MI mice exhibited greater cardiac conduction disturbances compared to wild-type MI mice.
• Histological damage to myocardial tissue was significantly increased in APOM-deficient animals.
• Inflammatory responses were markedly enhanced in the absence of APOM following MI.

Loss of APOM upregulates the acute-phase protein Saa1 and triggers NF-κB phosphorylation and nuclear translocation.

• Nuclear-cytoplasmic fractionation, immunofluorescence, and Western blot were used to investigate these signaling effects.
• APOM deficiency led to upregulation of Saa1 (serum amyloid A1), an acute-phase inflammatory protein.
• NF-κB phosphorylation and subsequent nuclear translocation were observed as downstream consequences of APOM loss.
• These events enhanced inflammasome-related inflammatory signaling and mediated cytokine release from cardiomyocytes.

APOM deficiency led to a significant decrease in sphingosine-1-phosphate (S1P), myocardial lipid droplet accumulation, and metabolite changes.

• S1P levels were significantly reduced in APOM-deficient mice, indicating disrupted sphingolipid metabolism.
• Myocardial lipid droplet accumulation was observed histologically in APOM-KO mice following MI.
• Metabolite changes consistent with lipid metabolic disorders were documented alongside the lipid droplet findings.
• APOM is known to serve as a carrier for S1P, providing a mechanistic link between APOM loss and S1P reduction.

Loss of APOM increased the expression of D-dimer and fibrinogen family proteins, indicating coagulation-associated alterations.

• Elevated D-dimer expression was observed in APOM-deficient mice, suggesting enhanced fibrinolysis or coagulation activity.
• Fibrinogen family protein expression was also increased following APOM loss.
• These coagulation-associated changes were identified as an additional mechanism by which APOM deficiency may worsen myocardial injury.

APOM is proposed as a potential cardioprotective agent and therapeutic target for brain-heart syndrome following acute ischemic stroke.

• The authors conclude that 'APOM may represent a potential therapeutic target for the intervention of brain-heart syndrome.'
• Downregulation of APOM was linked to multiple injury mechanisms: Saa1 elevation, NF-κB activation, inflammasome signaling, lipid metabolic disorders, and coagulation alterations.
• The convergence of clinical data, mouse models, proteomics, and mechanistic experiments supports APOM's cardioprotective role post-AIS.