Low androgen levels induce ferroptosis of rat penile cavernous endothelial cells

Hong-Xing Shi; Xin Zhao; Haifan Yang; Yong Cheng; Jun Jiang; Rui Jiang

doi:10.1093/sexmed/qfad043

Low androgen levels induce ferroptosis of rat penile cavernous endothelial cells

Sex Med. 2023 Aug 4;11(4):qfad043. doi: 10.1093/sexmed/qfad043. eCollection 2023 Aug.

Authors

Hong-Xing Shi¹, Xin Zhao¹, Haifan Yang¹, Yong Cheng¹, Jun Jiang², Rui Jiang^{1

3}

Affiliations

¹ Department of Urology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
² Department of Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
³ Nephropathy Clinical Medical Research Center of Sichuan Province, Affiliated Hospital, Southwest Medical University, Taiping Road, Luzhou, Sichuan 646000, China.

Abstract

Background: Endothelial dysfunction caused by low androgen levels in penile tissue can lead to erectile dysfunction. The exact mechanism of endothelial dysfunction has not been thoroughly studied.

Objective: The study sought to verify whether low androgen levels induce ferroptosis of endothelial cells in rat penile tissue.

Methods: Rat penile cavernous endothelial cells (CP-R133) were divided into a no-androgen group (Dihydrotestosterone (DHT): 0 nmol/L), very low-androgen group (DHT: 0.1 nmol/L), low-androgen group (DHT: 1 nmol/L), DHT = 10 nmol/L group, DHT (0 nmol/L) + ferrostatin-1 (Fer-1) group, DHT (0.1 nmol/L) + Fer-1 group, DHT (1 nmol/L) + Fer-1 group, DHT (10 nmol/L) + Fer-1 group. Cell viability, intracellular ferrous ion (Fe²⁺), malondialdehyde (MDA), GSH into oxidized glutathione (GSSG), reactive oxygen species (ROS), nitric oxide (NO), transferrin receptor 1 protein (TfR1), solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), endothelial nitric oxide synthase (eNOS), and phospho-eNOS (p-eNOS) were detected.

Outcomes: Low androgen levels could induce ferroptosis of rat penile cavernous endothelial cells in vivo by upregulating the expressions of TfR1 and ACSL4 and downregulating the expressions of SLC7A11 and GPX4.

Results: Cell viability, the levels of glutathione (GSH), NO, SLC7A11, GPX4, and p-eNOS/eNOS in the DHT = 0 nmol/L group were lower than those in the other groups (P < .05). The levels of Fe²⁺, ROS, MDA, GSSG, TfR1, and ACSL4 in the DHT = 0 nmol/L group were higher than those in the other groups (P < .05). Cell viability and the levels of GSH, NO, SLC7A11, GPX4, and p-eNOS/eNOS in the DHT = 1 nmol/L group were lower than those in the DHT (1 nmol/L) + Fer-1 group, DHT = 10 nmol/L group, and DHT (10 nmol/L) + Fer-1 group (P < .05). The levels of Fe²⁺, ROS, MDA, GSSG, TfR1, and ACSL4 in the DHT = 1 nmol/L group were higher than those in the DHT (1 nmol/L) + Fer-1 group, DHT = 10 nmol/L group, and DHT (10 nmol/L) + Fer-1 group (P < .05).

Clinical implications: A ferroptosis inhibitor might be a novel drug for treating erectile dysfunction caused by low androgen level.

Strengths and limitations: The results of this study need to be further confirmed in in vitro and in human studies. Meanwhile, further investigation is needed to clarify whether low androgen levels affect ferroptosis of rat penile cavernous smooth muscle and nerve cells.

Conclusion: Low androgen levels can induce ferroptosis of endothelial cells in rat penile tissue. Inhibition of ferroptosis can reverse endothelial dysfunction caused by low androgen levels.

Keywords: NO; androgen; endothelial cells; ferroptosis.