Ferroptosis is involved in corpus cavernosum smooth muscle cells impairment in diabetes mellitus‐induced erectile dysfunction

Abstract

Backgrounds: Erectile dysfunction (ED) is a common andrological disorder that tends to afflict diabetic patients, among others. Pharmacological therapy of diabetes mellitus-induced ED (DMED) is ineffective, as it is linked with smooth muscle cell loss in the corpus cavernosum. Ferroptosis is a recently identified kind of cell death evoked by lipid peroxidation, and it is connected with a number of diabetic complications.Objectives: To investigate the role of ferroptosis in DMED. Materials and methods:We established the rat model of DMED and conducted a combined analysis of RNA sequencing (RNA-seq) and Gene Expression Omnibus (GEO) data to identify differentially expressed genes (DEGs). Next, DMED disease targets were determined by cross-referencing DEGs and DMED-related genes in the DisGeNET, GenCLiP3, and GeneCards databases. Additionally, these targets were analyzed using "clusterProfiler" in R utilizing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations. Immunohistochemistry (IHC) staining of rat penile tissues was used to validate several targets. Notably, the Cell Counting Kit-8 assay, Western blotting, oxidative stress (OS) level, and iron concentration were tested in corpus cavernosum smooth muscle cells (CCSMCs) stimulated with high glucose (HG), and treated with Ferrostatin-1 (Fer-1).Results: Sixty-nine disease targets of DMED were identified. According to KEGG analysis, these targets were primarily enriched in the ferroptosis pathway. Additionally, IHC results revealed that the expression of GPX4, SLC7A11, and ACSL4 was deregulated in the DMED group compared to the control group. Significantly, HG decreased cell viability and increased OS and iron levels in CCSMCs, which could be reversed by Fer-1 treatment. Discussion and conclusion:Our study revealed that ferroptosis may indeed exist in DMED. GPX4, SLC7A11, and ACSL4 all have a role in controlling the viability of CCSMCs, making them potential therapeutic targets.

Overexpression of PRDX2 in Adipose-Derived Mesenchymal Stem Cells Enhances the Therapeutic Effect in a Neurogenic Erectile Dysfunction Rat Model by Inhibiting Ferroptosis

“…Recent studies have demonstrated that ferroptosis is related to the OS of CCSMCs in diabetes mellitus-induced ED and that human umbilical cord mesenchymal stem cells could treat diabetes mellitus-induced ED by inhibiting OS via attenuation of ferroptosis [ 36 , 37 ]. Similarly, we were surprised to find that the total iron ( Figure 6(e) ) and MDA ( Figure 6(f) ) contents in the PBS group were significantly higher than those in the sham group ( P < 0.05).…”

Identifying potential cross‐talk signatures for the occurrence of atherosclerosis in diabetic erectile dysfunction

“…39 And ferroptosis strengthened the connectivity relevance to oxidative stress, inflammation, and cardiovascular diseases. 36 Similarly, Xu et al 40,41 reported that ferroptosis was responsible for the corpus cavernosum smooth muscle cells impairment in DMED, and GPX4 was feasible for the treatment of DMED via inhibiting ferroptosis. Besides, autophagy was noticed in the process of DMED, and autophagosomes, as well as…”

A review of experimental techniques for erectile function researches and development of medical technology using animal erectile dysfunction models in sexual and reproductive medicine

“…[25][26][27] In addition, comprehensive analysis methods such as microarrays and RNA sequencing (RNA-seq) have been developed, making it possible to evaluate factors that have not been studied in the past, leading to rapid progress in research. 28,29 Western blotting has also been used to measure protein expression levels, and significant progress has been made with the development of enzyme-linked immunosorbent assay (ELISA) kits and quantification methods using liquid chromatography-mass spectrometry (LC-MS) to measure protein levels. [30][31][32] In basic research on sexual function, the animal species used are changing along with the development of research methods.…”