Integrative Transcriptomic Analysis Identifies GPX3 and CSF3R as Candidate Markers of Diabetes-Associated Myocardial Injury
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Jiayi Song1, Yiyin Long1, Wujing Zhang1
1Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China.
Purpose:
The clinical relationship between diabetes mellitus (DM) and myocardial injury (MI) is well established, yet the antioxidant protection mechanisms involving glutathione peroxidase that link DM to MI remain insufficiently characterized. Here, across multiple organs and tissues, we explored the relationship between extracellular antioxidant defense and inflammatory signaling in DM-induced MI.
Methods:
The analyses integrated six single-cell RNA-seq datasets (21 diabetic samples; 122,801 cells) with the bulk transcriptomic dataset GSE184050 (113 samples); LASSO regression yielded a cross-validated area under the curve (AUC) of 0.701, and GPX3 and CSF3R were further validated in a T2DM-AS mouse model (n = 3 per group for histological and Western blot analyses).
Results:
We identified glutathione peroxidase 3 (GPX3) and colony-stimulating factor 3 receptor (CSF3R) as candidate markers associated with DM-induced MI. CSF3R was enriched in injury- and inflammation-related pathways including PI3K-Akt signaling, whereas GPX3 was enriched in antioxidant and defense-related pathways. CSF3R enrichment was also associated with reduced activity of the cardioprotective cGMP-PKG pathway. Endothelial dysfunction and collagen remodeling, potentially involving monocyte-endothelial crosstalk, are proposed as candidate intermediates in this cascade. Histological examination confirmed extensive MI in DM mice, characterized by disordered cardiomyocyte arrangement and widespread myofiber rupture. Western blot analysis showed that myocardial GPX3 expression was significantly downregulated in DM mice compared with non-diabetic controls, whereas CSF3R was markedly upregulated, changes that were specific to the diabetic milieu and not observed in atherosclerosis alone.
Conclusion:
GPX3 and CSF3R were identified as candidate markers associated with diabetes-related cardiac injury and warrant validation in independent human cardiac datasets and mechanistic experiments.