Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Andrology. 2023 Feb;11(2):332-343. doi: 10.1111/andr.13291. Epub 2022 Sep 20.
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.
To investigate the role of ferroptosis in DMED.
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).
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.
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.
勃起功能障碍（ED）是一种常见的男科疾病，常影响糖尿病患者。糖尿病引起的 ED（DMED）的药物治疗无效，因为它与海绵体平滑肌细胞的丧失有关。铁死亡是一种最近发现的由脂质过氧化引起的细胞死亡方式，与许多糖尿病并发症有关。
探讨铁死亡在 DMED 中的作用。
我们建立了 DMED 大鼠模型，并进行了 RNA 测序（RNA-seq）和基因表达综合数据库（GEO）数据的联合分析，以鉴定差异表达基因（DEGs）。接下来，通过交叉参考 DisGeNET、GenCLiP3 和 GeneCards 数据库中的 DEGs 和 DMED 相关基因，确定 DMED 疾病靶点。此外，还使用 R 中的“clusterProfiler”对这些靶点进行了基因本体论（GO）和京都基因与基因组百科全书（KEGG）注释分析。使用免疫组织化学（IHC）染色大鼠阴茎组织验证了几个靶点。值得注意的是，在高糖（HG）刺激的海绵体平滑肌细胞（CCSMCs）中，使用细胞计数试剂盒-8 检测（CCK-8）、Western blot、氧化应激（OS）水平和铁浓度，并用 Ferrostatine-1（Fer-1）处理。
鉴定出 69 个 DMED 的疾病靶点。根据 KEGG 分析，这些靶点主要富集在铁死亡途径中。此外，IHC 结果显示，与对照组相比，DMED 组中 GPX4、SLC7A11 和 ACSL4 的表达失调。显著的是，HG 降低了 CCSMCs 的细胞活力，并增加了 OS 和铁水平，Fer-1 处理可逆转这一结果。
我们的研究表明，铁死亡可能确实存在于 DMED 中。GPX4、SLC7A11 和 ACSL4 均在控制 CCSMCs 活力方面发挥作用，使其成为潜在的治疗靶点。
