Icariin inhibits hyperglycemia-induced cell death in penile cavernous tissue and improves erectile function in type 1 diabetic rats

Background Hyperglycemia can cause endothelial cell (EC) and smooth muscle cell (SMC) death in the penile cavernous tissue of rats and lead to erectile dysfunction (ED).Objectives To investigate the proportions of apoptotic, pyroptotic, and ferroptotic cells among ECs and SMCs in the penile cavernous tissue of type 1 diabetic (T1DM) rats and the mechanism by which icariin (ICA) improves the erectile function of T1DM rats.Methods A total of 24 9-week-old Sprague-Dawley (SD) rats were randomly divided into 4 groups (n = 6): control group, control + ICA group, diabetic mellitus (DM) group, and DM + ICA group. T1DM rats were generated via the intraperitoneal injection of STZ (45 mg/kg). After 8 weeks, the rats in the control + ICA group and the DM + ICA group were administered ICA (10 mg/kg/d) by gavage for 4 weeks. ROS, MDA, SOD, GSH, SM/C, and NO levels, and GPX4, ACSL4, caspase-1, GSDMD, caspase-3, CD31, alpha-SMA, and p-eNOS/eNOS expression in penile cavernous tissue and the ICPmax/MAP of 21-week-old rats were detected.Results The percentage of pyroptotic SMCs in penile cavernosum was no statistically significant difference among these groups. Vs control group, the percentages of apoptotic (20.70% +/- 1.60%), pyroptotic (21.02% +/- 1.97%), and ferroptotic (9.01% +/- 2.00%) ECs and the percentages of apoptotic (15.47% +/- 1.36%) and ferroptotic (26.33% +/- 3.11%) SMCs in the penile cavernous tissue of the DM group were significantly greater. Vs DM group, the percentages of apoptotic (9.13% +/- 1.28%), pyroptotic (13.22 +/- 1.26%), and ferroptotic (4.01% +/- 0.86%) ECs and the percentages of apoptotic (11.60% +/- 1.91%) and ferroptotic (12.71% +/- 2.92%) SMCs of the DM + ICA group were significantly lower. Vs the DM group, the levels of caspase-1, GSDMD, ACSL4, and ROS were significantly lower in the penile cavernous tissue of the DM + ICA group. Meanwhile, the levels of GPX4 and maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP) were significantly higher.Clinical Implications The combined inhibition of apoptosis, pyroptosis, and ferroptosis in penile cavernous tissue by ICA provides a theoretical basis for the clinical development of multi-target drugs for the treatment of type 1 diabetes-induced ED.Strengths and Limitations Further experiments are required to clarify whether other types of cell death are involved in the loss of ECs and SMCs in the penile cavernous tissue of T1DM rats.Conclusion Inhibiting oxidative stress and thereby inhibiting apoptosis, pyroptosis, and ferroptosis in ECs and SMCs of penile cavernous tissue constitute one of the mechanisms through which ICA improves erectile function in T1DM rats.