Exploring the role of glycolysis in the pathogenesis of erectile dysfunction in diabetes.

Background: Diabetes mellitus-related erectile dysfunction (DMED) is characterized by complicated pathogenesis and unsatisfactory therapeutic remedies. Glycolysis plays an essential role in diabetic complications and whether it is involved in the process of DMED has not been expounded. The aim of this study was to investigate the genetic profiling of glycolysis and explore potential mechanisms for DMED.

Methods: Glycolysis-related genes (GRGs) and gene expression matrix of DMED were obtained from the molecular signatures database and gene expression omnibus dataset. Differentially expressed analysis and support vector machine-recursive feature elimination (SVM-RFE) method were both used to obtain hub GRGs. Interactive network and functional enrichment analyses were performed to clarify the associated biological roles of these genes. The expression profile of hub GRGs was validated in cavernous endothelial cells, animals, and clinical patients. The subpopulation distribution of hub GRGs was further identified. In addition, a miRNA-GRGs network was constructed and expression patterns as well as molecular functions of relevant miRNAs were explored and validated. In addition, the relationship between hypoxia and DMED was also uncovered.

Results: Based on the combined analysis, 48 differentially expressed GRGs were obtained. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that these genes were significantly enriched in carbon metabolism and oxidoreductase activities. Then hub GRGs including down-regulated as well as up-regulated genes in DMED were identified ultimately. Among them, ALDOC, ANGPTL4, and CITED2 were well-validated. In addition, 334 glycolysis-related miRNAs were verified and they were involved in endoplasmic reticulum membrane activity, smooth muscle cell differentiation and angiogenesis. After validation of miRNA signature in DMED patients, miR-222-5p, let-7e-5p, miR-184, and miR-122-3p were identified as the promising glycolysis-related miRNA biomarkers in DMED.

Conclusions: We clarified the expression signature of GRGs in DMED based on multi-omics analysis for the first time. It will be significantly important to reveal pathological mechanisms and promising treatments in DMED.