Hydrogen Peroxide-Induced Re-Expression of Repressor Element 1-Silencing Transcription Factor Contributes to Cardiac Vagal Dysfunction in Type 2 Diabetes Mellitus

Diabetes mellitus, especially type 2 diabetes mellitus (T2DM), is a major health problem worldwide and has become a leading cause of mortality. As a common complication of patients with T2DM, cardiac autonomic dysfunction (including sympathetic overactivation and reduced vagal tone) is associated with a higher risk of arrhythmia-related sudden cardiac death. Our previous study found that T2DM-elevated hydrogen peroxide (H₂O₂) levels in atrioventricular ganglion (AVG) neurons contribute to the decrease in cardiac vagal function and ventricular arrhythmogenesis through inhibition of N-type Ca²⁺ channels (Ca_v2.2). In the present study, treatment with exogenous H₂O₂ in differentiated NG108-15 cells increased REST expression and decreased Ca_v2.2-α expression. Adenoviral catalase gene transfection into the AVG neurons significantly reduced the REST levels elevated by a high-fat diet plus streptozotocin-induced T2DM. Lentiviral REST shRNA transfection markedly increased Ca_v2.2-α expression in the AVG neurons from T2DM rats. REST shRNA also activated N-type Ca²⁺ channels and increased cell excitability of AVG neurons in T2DM rats. Additionally, REST shRNA markedly improved cardiac vagal activation in T2DM rats. The present study suggests that the H₂O₂-REST-Ca_v2.2 channel signaling axis could be a potential therapeutic target to normalize cardiac vagal dysfunction and its related cardiac complications in T2DM.