Epigenetic silencing of microRNA‐874‐3p implicates in erectile dysfunction in diabetic rats by activating the Nupr1/Chop‐mediated pathway

Abstract

Diabetes is a global medical problem that causes many deaths every year.Complications caused by diabetes are serious and affect patients' quality of life.Diabetes mellitus erectile dysfunction (DMED) affects more than half of male diabetes patients. In this study, we determined the role of microRNA-874-3p (miR-874-3p) and nuclear protein-1 (Nupr1) in streptozocin-induced DMED rats. Control rats received equal amount of vehicle. These rats were also injected with lentiviral vector or agomir to silence or overexpress miR-874-3p or Nupr1. Apomorphine (100 μg/kg, s.c.) was used to induce erection and time of erection was recorded. Intracavernosal and mean arterial pressure ratio (ICP/MAP) were also recorded. O 2− level and concentration of thiobarbituric acid reactive substances (TBARs) were detected using lucigenin-derived chemiluminescence method and Colorimetry. Rat cavernosum tissues were collected for subsequent experiments. Cavernosum smooth muscle cells (CSMCs) were also used for in vitro experiments. Nupr1 was found highly expressed (by RT-qPCR and Western blot analysis) in cavernosum tissues from DMED rats.Nupr1 silencing improved the ICP/MAP ratio and erection time. Nupr1 silencing also reduced CSMC apoptosis (by TUNEL assay) as well as decreased O 2− level and TBAR concentration. Nupr1 was targeted and inhibited by miR-874-3p (by luciferase activity and RNA immunoprecipitation assays), which was downregulated in DMED. miR-874-3p downregulation was due to increased methylation at the promoter region (methylation-specific PCR). miR-874-3p overexpression improved erection time and reduced apoptosis. In summary, miR-874-3p was downregulated which led to increased apoptosis and erectile dysfunction in DMED rats, through 1696 | HUO et al. | Establishment of STZ-induced DMED rat modelMale specific pathogen-free (SPF) Sprague-Dawley (SD) rats (n = 90, 8 wk old, 250-300 g) that had normal inhibition of Nupr1-mediated pathway. This study may also provide a new therapeutic direction for the treatment of DMED. K E Y W O R D SChop, diabetic erectile dysfunction, microRNA-874-3p, Nupr1

Circ_0040039 May Aggravate Intervertebral Disk Degeneration by Regulating the MiR-874-3p-ESR1 Pathway

“…Huang et al (2018) found that silencing circ_0000977 promoted the apoptosis of pancreatic ductal adenocarcinoma cells by stimulating miR-874-3p and inhibiting PLK1 expression. However, miR-874-3p has been confirmed to inhibit the apoptosis of brain tissue (Jiang et al, 2019;Xie et al, 2020) and cavernosal smooth muscle cells (Huo et al, 2020). The different roles of miR-874-3p may be related to cell state and type.…”

Identification of miRNA Signature Associated With Erectile Dysfunction in Type 2 Diabetes Mellitus by Support Vector Machine-Recursive Feature Elimination

“…Many pieces of evidence have shown that miRNAs have diagnostic and predictive value for DMED in mice ( Li et al, 2017 ; Cong et al, 2020 ; Huo et al, 2020 ). However, few correlational researches of DMED have been conducted on the human body.…”

Upregulation of T Cell Receptor Signaling Pathway Components in Gestational Diabetes Mellitus Patients: Joint Analysis of mRNA and circRNA Expression Profiles

“…The constructed ceRNA network predicted that both miR-874-3p and miR-339-5p significantly interacted with circ-ICAM1. Huo et al found that the expression of miR-874-3p in diabetic rats was significantly downregulated, which led to increased islet b cell apoptosis and diabetes-induced erectile dysfunction by targeting the inhibition of the nuclear protein 1 (Nupr1)-mediated pathway (62). It was also observed that miR-339-5p and miR-874-3p mediate high glucose-induced endothelial inflammation by targeting interleukin-1 receptorassociated kinase 1 (IRAK1) expression (63).…”