Simvastatin alleviated diabetes mellitus-induced erectile dysfunction in rats by enhancing AMPK pathway-induced autophagy.Andrology 2020A
Diabetes mellitus-induced erectile dysfunction (DMED) is a common diabetic complication, and new therapeutics and the pathogenesis of DMED need to be investigated.
The aim was to investigate the pathogenesis of DMED and the pharmacological mechanism of simvastatin treatment in DMED model rats.
MATERIALS AND METHODS
A total of 86 male Sprague-Dawley (SD) rats aged 8 weeks old were used in this study. The rats were divided into 3 groups: control (normal), DMED (streptozotocin (STZ) -injected), and DMED+simvastatin (sim). Each group was subdivided into 2 subgroups for in vitro and in vivo analyses. A bioinformatics method was used to detect differences in gene expression in the corpus cavernosum between normal and DMED rats. Erectile function was measured by a cavernous nerve (CN) electrostimulation test. Corpus cavernosum fibrosis was assessed by Masson staining and Western blotting. Immunofluorescence and Western blotting were performed to explore the differential expression of autophagy-related genes and the AMPK-SKP2-CARM1 pathway genes in rat cavernous smooth muscle cells (CSMCs) and the corpus cavernosum. The autophagosomes of the corpus cavernosum tissue were observed by transmission electron microscopy.
Autophagy-related genes and pathways (the AMPK and FoxO pathway) were identified by bioinformatics analysis and confirmed at the protein level. Simvastatin, an AMPK agonist, was used to treat DMED rats for 8 weeks, demonstrating that erectile function was improved for 80.5% (P < 0.05) of rats. Corpus cavernosum fibrosis was alleviated (P < 0.05), and autophagy was further enhanced (P < 0.05); these results might be partially caused by AMPK-SKP2-CARM1 pathway activation (P < 0.05).
DISCUSSION AND CONCLUSION
Simvastatin could enhance protective autophagy by activating the AMPK-SKP2-CARM1 pathway to improve erectile function in DMED rats.