(090) Hydrogen Sulfide Therapy Stimulates Cellular Antioxidant Defense and Reverses Erectile Dysfunction in Western Diet-fed Mice (2023)

Abstract Introduction Hydrogen sulfide (H2S) is an endogenously produced gaseous cellular signaling molecule with vasodilatory, anti-inflammatory, and antioxidant-like properties. H2S is thought to protect against oxidative stress through activation of transcription factor(s) that transcribe genes involved cellular detoxification and antioxidant defense. We have previously used a Western diet (WD) high in fat and sugar to induce erectile dysfunction (ED) in rodents, in which excessive penile reactive oxygen species (ROS) have been implicated in ED pathogenesis. We have recently observed a reduction in protein content and activity of cystathionine γ-lyase, a major enzymatic source of H2S, in the corpus cavernosum of mice fed the WD for 12 weeks. Objective The objective of this study was to determine if chronic consumption of an orally active, slow releasing H2S prodrug (SG1002) can restore erectile function and alleviate WD-induced penile redox burden. Methods Young male C57Bl/6J mice (n = 120) were fed a control diet (CD) or WD ad libitum for 18 weeks. For the final six weeks of the dietary intervention, half of the mice were switched to an equivalent diet containing SG1002 at a concentration designed to deliver approximately 20 mg/kg/day. Following the intervention, erectile function was assessed by measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP) during cavernous nerve stimulation (1, 2, 4 volts). In separate mice, in vivo ROS production was measured in the penis utilizing a microdialysis approach. Microdialysis probes were inserted into the penis of anesthetized mice and perfused with saline containing 100 μM Amplex Ultrared, 1 U/ml horseradish peroxidase, and 10 U/ml superoxide dismutase. ROS convert the reagents to a fluorescent byproduct resorufin, which was measured in the outflowing dialysate. In separate mice, naïve corpus cavernosum tissue was harvested for quantitative expression of 18 genes related to cellular antioxidant defense by qRT-PCR. Significant differences between groups were determined by two-way ANOVA with Tukey’s multiple comparisons post-hoc analysis, with an alpha level of 0.05. Results Erectile function was significantly impaired in the untreated WD-fed mice (CD: 64.8±8.4 vs. WD: 27.1±2.3; cumulative ICP area/MAP; p&amp;lt;0.01), while SG1002 induced a 74% functional restoration in WD mice (WD+SG1002: 51.0±2.8; p&amp;lt;0.05 vs. WD). Penile production of the ROS hydrogen peroxide and superoxide were elevated in the WD mice (CD: 0.71±0.07 vs. WD: 1.09 ±0.15; p&amp;lt;0.01), which were normalized by SG1002 treatment (WD+SG1002: 0.83±0.07; p&amp;lt;0.01 vs. WD). SG1002 had a positive stimulatory effect (p&amp;lt;0.05) on expression of ten of the antioxidant genes, including catalase, glutamate-cysteine ligase (gclc), glutathione peroxidase 1, glutathione peroxidase 4, peroxiredoxin 3, peroxiredoxin 5, thioredoxin reductase 1, heme oxygenase 1, sirtuin 1, and sirtuin 3. Conclusions H2S therapy with chronic SG1002 administration provides protection to the corpus cavernosum against an excessive ROS burden induced by the high-fat/high-sugar environment of the Western diet, likely through augmentation of the cellular antioxidant defense system. H2S therapy may be a promising strategy for treatment of early stage, obesity-associated erectile dysfunction. Disclosure No