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

Low androgen levels induce ferroptosis of rat penile cavernous endothelial cells

Hong-Xing Shi  1 , Xin Zhao  1 , Haifan Yang  1 , Yong Cheng  1 , Jun Jiang  2 , Rui Jiang  1   3
Affiliations

Low androgen levels induce ferroptosis of rat penile cavernous endothelial cells

Hong-Xing Shi et al. Sex Med. .

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.

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Figures

Figure 1
Figure 1
Cell viability and iron content in each group. (A) Cell viability was detected by CCK-8. (B) Iron content was detected by the iron assay kit. *P < .05 vs the no-androgen group; #P < .05 vs the low-androgen group.
Figure 2
Figure 2
The generation of reactive oxygen species (ROS) was determined in each group. (A) Histogram was used to present ROS levels. (B) Data are presented as the relative ROS levels in each group. *P < .05 vs the no-androgen group; #P < .05 vs the low-androgen group.
Figure 3
Figure 3
The expressions of GPX4, x-CT, TfR1, ACSL4, endothelial nitric oxide synthase (e-NOS), and phospho-eNOS (p-eNOS) in rat penile cavernous endothelial cells. (A) The analyses of GPX4, x-CT, TfR1, ACSL4, e-NOS and p-eNOS were by Western blotting in each group. (B) Data are presented as the relative density values of GPX4, x-CT, TfR1, ACSL4, e-NOS, and p-eNOS. (C) Data are presented as the ratio of p-eNOS/eNOS. *P < .05 vs the no-androgen group; #P < .05 vs the low-androgen group.
Figure 4
Figure 4
The concentrations of GSH, oxidized GSH (GSSG), malondialdehyde (MDA), and nitric oxide (NO) were detected in each group. (A) Data are presented as the concentration of GSH in each group; (B) data are presented as the concentration of GSSG in each group; (C) data are presented as the concentration of MDA in each group; (D) data are presented as the concentration of NO in each group. *P < .05 vs the no-androgen group; #P < .05 vs the low-androgen group.
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