Silenced SOX2-OT alleviates ventricular arrhythmia associated with heart failure by inhibiting NLRP3 expression via regulating miR-2355-3p.

Background: Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes are the most important factors in ventricular arrhythmia associated with heart failure (VA-HF). However, how the relationship between lncRNA and NLRP3 inflammasomes is regulated in VA-HF has not been investigated in detail. Thus, we aimed to determine the effects of SOX2-overlapping transcripts (SOX2-OT) by targeting NLRP3 in rats with VA-HF.

Methods: We established rats (SPF, male, weight: 240 ± 10 g) with VA-HF by aortic coarctation and constant-current stimulation, then injected them with small interfering SOX2-OT and anti-miR-2355-3p. Six weeks later, SOX2-OT and miR-2355-3p expression was measured using the quantitative reverse transcriptase-polymerase chain reaction and NLRP3, ASC, caspase-1, IL-1β, and TGF-β1 expression were measured by Western blot analysis; the ventricular chambers were histopathologically analyzed by staining with hematoxylin and eosin, Masson trichrome, and Picro Sirius Red and reactive oxygen species (ROS) levels were assessed by flow cytometry. The targeting relationship between miR-2355-3p and SOX2-OT or NLRP3 was verified using dual-luciferase reporter gene assays.

Results: The expression of SOX2-OT and levels of NLRP3 inflammasomes gradually increased in normal rats, and in those with heart failure and with VA-HF. Silencing SOX2-OT expression inhibited NLRP3, ASC, caspase-1, IL-1β, and TGF-β1 expression and ROS production, reduced the degrees of cardiomyocyte necrosis and fibrosis and alleviated cardiac dysfunction in rats with VA-HF. MicroR-2355-3p can bind the SOX2-OT and the 3'-untranslated region of NLRP3. Inhibiting miR-2355-3p reversed the effect of SOX2-OT in rats with VA-HF.

Conclusions: Silencing SOX2-OT alleviated cardiac dysfunction in rats by reducing the activation of NLRP3 inflammasomes via regulating miR-2355-3p.