Hypoandrogenic state inhibits erectile function in rats via miR-200a-3p.

Abstract

Background: Androgen deficiency is an important cause of erectile dysfunction (ED), and miRNAs are small-molecule RNAs with multiple biological functions. However, whether androgen deficiency affects erectile function by regulating miRNAs is unknown.

Aim: The aim of the study was to investigate the differential expression of key miRNAs in the penile corpus cavernosum of castrated rats and the relationship between these miRNAs and erectile function.

Methods: The expression of key miRNAs in the penile corpus cavernosum of sham-operated, castration-operated, and post-castration testosterone replacement-treated rats was detected via high-throughput sequencing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to identify significantly up-regulated and down-regulated miRNAs in the penile corpus cavernosum of castrated rats, functional assays and prediction and validation of target genes were performed for key miRNAs, and the relationships between the expression of key microRNAs and maximum intracavernous pressure/mean arterial pressure ratio (ICPmax/MAP) were examined.

Outcomes: Significant up-regulation of miR-200a-3p in the penile corpus cavernosum of castrated rats leads to ED by activating the RhoA/Rho-kinase signaling pathway and inhibiting p-eNOS/eNOS.

Results: Among these miRNAs, the expression of miR-200a-3p was significantly greater in the penile corpus cavernosum of the cast group (50.67 ± 6.91) than in that of the sham group (1.00 ± 0.09) and the cast+T group (2.07 ± 0.35) (P < 0.05). Dlc1 and p-eNOS/eNOS in the penile corpus cavernosum of the cast group were significantly lower than those of the sham and cast+T groups (P < 0.05). The over-expression of miR-200a-3p significantly inhibited the expression of Dlc1 and decreased p-eNOS/eNOS and ICPmax/MAP (P < 0.05). Inhibition of miR-200a-3p significantly up-regulated the expression of Dlc1 and elevated the ICPmax/MAP (P < 0.05).

Clinical implications: Inhibition of miR-200a-3p expression and function in the penile corpus cavernosum may be a potential treatment for ED due to androgen deficiency.

Strengths and limitations: This study revealed that miR-200a-3p can lead to ED by affecting the RhoA/Rho-kinase and eNOS/NO signaling pathways. However, the specific mechanism of miR-200a-3prole in ED needs to be further investigated.

Conclusion: Significant up-regulation of miR-200a-3p in the penile corpus cavernosum of castrated rats inhibited Dlc1 expression, which activated the RhoA/Rho-kinase signaling pathway in smooth muscle cells and inhibited p-eNOS/eNOS in endothelial cells to suppress erectile function. Inhibiting endogenous miR-200a-3p in the penile corpus cavernosum of castrated rats may improve erectile function.