Pyroptosis and inflammation­mediated endothelial dysfunction may act as key factors in the development of erectile dysfunction (Review).

Erectile dysfunction (ED) is a prevalent disease that causes sexual dysfunction in males. Inflammation­induced endothelial dysfunction is a fundamental pathophysiological symptom of ED, which is impacted by cell death. Pyroptosis is a type of programmed cell death mediated by the inflammasome that was discovered in inflammatory disorders. The activation of nucleotide­binding oligomerization domain­like receptors, particularly downstream inflammatory factors, such as IL­1ß and IL­18, is indicative of caspase­dependent pyroptosis. Although the underlying mechanisms of pyroptosis have been investigated in several disorders, the role of pyroptosis in ED remains to be fully elucidated. At present, studies on pyroptosis have focused on improving the understanding of ED pathogenesis and promoting the development of novel therapeutic options. The present review article aimed to discuss the literature surrounding the mechanisms underlying pyroptosis, and summarize the role of pyroptosis in the development and progression of inflammation­mediated ED.

Exploring the application of sildenafil for high-fat diet-induced erectile dysfunction based on interleukin-18-mediated NLRP3/Caspase-1 signaling pathway.

Background: Inflammation is a key risk factor for heart disease and has also been linked to erectile dysfunction (ED). Sildenafil is a phosphodiesterase type 5 inhibitor with a strong antioxidant effect. Interleukin (IL)-18 is a proinflammatory factor. Excessive production and release of IL-18 disrupt the balance between IL-18 and IL-18 binding proteins in certain inflammatory diseases, leading to the occurrence of pathological inflammation. Aim: We evaluated the effects of sildenafil on erectile function in a rat model of high-fat diet-induced ED. Methods: Male Sprague Dawley rats (6 weeks old) were divided into 5 groups: control, ED, sildenafil, IL-18, and IL-18 + sildenafil. Subsequently, intracavernous pressure and mean arterial pressure were used to assess the erectile function of these rats. The expression of endothelial nitric oxide synthase, pyroptosis factors, and the ratio of smooth muscle cells and collagen fibers were evaluated in the serum and corpora tissue. Outcomes: Exploring the role and mechanism of sildenafil in ED through NLRP3-mediated pyroptosis pathway. Results: In comparison to the ED and IL-18 groups, there were statistically significant increases in the ratio of intracavernous pressure to mean arterial pressure, endothelial nitric oxide synthase expression, and the ratio of smooth muscle cells to collagen fibers following sildenafil intervention (P < .05). The sildenafil group and IL-18 + sildenafil group also showed statistically significant decreases the expression of NLRP3, caspase-1, and gasdermin D (P < .05). Clinical Implications: Sildenafil can improve erectile dysfunction by inhibiting inflammation. Strengths and Limitations: Strengths are that the relationship between pyroptosis and ED has been verified through in vitro and in vivo experiments. The limitation is that the conclusions drawn from animal and cells experiments need to be confirmed in clinical research. Conclusion: Sildenafil may reduce the effect of IL-18-induced inflammation in high-fat diet-induced ED rats through NLRP3/caspase-1 pyroptosis pathway.