PurposeHeart disease is a major cause of mortality and disability worldwide. Melatonin is a neuroendocrine hormone and has been found to be protective in heart disease. However, the molecular basis underlying this cardioprotective effect is not fully understood. Here we aim to investigate melatonin-sensitive genes in cardiovascular system using public gene expression databases.MethodsAn innovative genomic analysis method, the weighted gene co-expression network analysis (WGCNA) combined with differential gene expression analysis, was used in this study. The algorithm was implemented in R/Bioconductor.ResultsUsing this method, we provide a comprehensive characterization of transcriptional profiles associated with melatonin treatment. We found that 357 differentially expressed genes (DEGs) were highly sensitive to melatonin in mouse myocardium. Enrichment analysis showed that these 357 genes were mostly related to GO:0051984 (positive regulation of chromosome segregation), GO:0016605 (PML body) and GO:0006281 (DNA repair). We further obtained 5 hub genes from the 357 DEGs, including Set, Dhx40, Scaf11, Cfh, and Nup43.ConclusionsWe identified numerous melatonin-sensitive genes and further identified five hub genes. The five novel genes are possibly associated with the myocardial benefits of melatonin.