Cardiac transcriptomics identifies S100A8/A9 as novel dual biomarkers and therapeutic targets for acute myocardial ischemia

Postmortem diagnosis of acute myocardial ischemia (AMI) within the first 6 h remains difficult in both clinical and forensic practice because early myocardial histological changes are often nonspecific. This study aimed to identify biomarkers for AMI in autopsy tissues and to preliminarily explore their roles in ischemic injury. Herein, we reanalyzed a previously generated RNA-seq dataset from a mouse model of AMI and sham controls to identify differentially expressed genes (DEGs). Candidate molecules were validated using RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence in both in vivo and in vitro AMI models. Additionally, their diagnostic value was evaluated using receiver operating characteristic (ROC) curve analysis in human cardiac tissue samples. Reanalyzed identified 593 differentially expressed genes (501 upregulated, 92 downregulated) between AMI and sham mice. RT-qPCR confirmed significant upregulation of S100A8 and S100A9, which increased progressively with early ischemia in mouse myocardium and under hypoxia in AC16 cells. In human samples, immunohistochemistry showed markedly higher S100A8/A9 expression in AMI compared with controls, independent of age and postmortem interval. ROC analysis highlighted the diagnostic potential of S100A8/A9 for AMI, with combined detection achieving optimal sensitivity (91.3%) and an AUC of 0.8092 in differentiating AMI from controls. Notably, treatment with the S100A8/A9-specific inhibitor Paquinimod effectively alleviated hypoxia-induced cardiomyocyte apoptosis, mitochondrial dysfunction, and inflammatory responses, indicating a pivotal role of S100A8/9 in myocardial ischemic injury. Overall, our findings indicate that S100A8/A9 may serve as valuable postmortem diagnostic markers for AMI and represent promising therapeutic targets for mitigating AMI-induced myocardial damage.