Upregulated FTO promotes TNIP1 m6A demethylation induced penile corpus cavernosum endothelial pyroptosis and erectile...

Erectile dysfunction (ED) is a prevalent complication of type 2 diabetes mellitus (T2DM). However, the role of RNA N6-methyladenosine (m6A) methylation in T2DM-associated ED remains unclear.

To determine whether m6A demethylation of TNFAIP3-interacting protein 1 (TNIP1) RNA mediated by fat mass and obesity-associated protein (FTO) regulates pyroptosis in corpus cavernosum endothelial cells in T2DM and contributes to ED.

The endothelial cells of the penile corpus cavernosum were obtained from Sprague-Dawley (SD) rats aged 8 weeks and assigned to five groups as follows: Control group, KD-FTO group that treated with the FTO-targeting siRNA lentivirus, OE-FTO group that treated with the FTO-overexpression lentiviral vector, KD-NC group that treated with the control siRNA lentivirus, and OE-NC group that treated with the empty FTO-overexpression lentiviral vector. The levels of FTO, TNIP1, NFκB, caspase-1, p-eNOS/eNOS, and NO were measured. TNIP1 mRNA stability was assessed. Male SD rats aged 8 weeks were randomly allocated to six groups: Control group, NC + Con group that SD rats treated with the empty lentivirus, NC + FTO-OE group that SD rats treated with the lentiviral vector carrying an over-expressed FTO gene, T2DM rats, T2DM + Con group that T2DM rats treated with the empty lentivirus, and T2DM + FTO-KD group that T2DM rats treated with the lentivirus carrying an siRNA targeting FTO. Two weeks after injection, the expression of FTO, TNIP1, caspase-1, p-eNOS/eNOS, as well as the ratio of pyroptotic endothelial cells in the penile corpus cavernosum, was evaluated.

Upregulation of FTO in the penile corpus cavernosum of T2DM rats promoted m6A demethylation of TNIP1 mRNA, decreased TNIP1 expression, and enhanced the NFκB/caspase-1 pathway, thereby increasing endothelial pyroptosis and reducing ED.

Compared with the NC group, the T2DM group exhibited significantly increased FTO expression, whereas global RNA m6A methylation, ICPmax/MAP, p-eNOS/eNOS, and NO levels were significantly decreased (P < .05). Compared with the T2DM group, the T2DM + FTO-KD group showed markedly higher TNIP1 levels, p-eNOS/eNOS, and ICPmax/MAP, accompanied by reduced expression of FTO, NFκB, caspase-1, and significantly lower pyroptotic endothelial cells (P < .05).

Targeting FTO-mediated TNIP1 m6A demethylation may offer a therapeutic strategy for T2DM-associated ED.

Other m6A regulators potentially involved in this process were not assessed.

In T2DM, upregulated FTO promoted m6A demethylation of TNIP1 mRNA, downregulated TNIP1 expression, enhanced NFκB/caspase-1 signaling, and increased endothelial cell pyroptosis in the penile corpus cavernosum, thereby contributing to ED.