H2O2-REST signaling pathway is involved in cardiac vagal dysfunction and myocardial infarction-evoked ventricular arrhythmia in type 2 diabetes

Myocardial infarction (MI)-induced ventricular arrhythmia is the most common cause of death in patients with type 2 diabetes mellitus (T2DM). Patients with T2DM are two to four times more likely to die from MI than non-diabetic patients. Withdrawal of cardiac vagal activity is an important trigger for MI-induced ventricular arrhythmias in T2DM. Our recent study found that T2DM-elevated hydrogen peroxide (H2O2) levels in cardiac vagal postganglionic (CVP) neurons contribute to the withdrawal of cardiac vagal activity and ventricular arrhythmogenesis through inhibition of N-type Ca2+ channels (Cav2.2) in CVP neurons. The repressor element 1-silencing transcription factor (REST) is crucial to inhibit the expression of Cav2.2-α. In general, mature neuronal cells do not express the REST in the physiological condition. Here, we tested whether H2O2 induces REST expression in CVP neurons, which successively inhibits the expression of Cav2.2 in CVP neurons, causes cardiac vagal dysfunction, and triggers MI-evoked ventricular arrhythmias in T2DM rats. Our in vitro experiments demonstrated that protein expression of REST is high, whereas Cav2.2-α expression is low in undifferentiated NG108-15 cells. Differentiation of NG108-15 cells for twenty-one days significantly reduced REST expression and increased Cav2.2-α expression. Additionally, treatment with exogenous H2O2 (1 μM) in differentiated NG108-15 cells markedly increased REST expression and decreased Cav2.2-α expression. Similarly, a high level of REST protein and a low level of Cav2.2-α protein were confirmed in CVP neurons from T2DM rats than those from age-matched sham rats. In vivo transfection of REST shRNA (2 μl, 1×107 TU/ml) into the CVP neurons significantly decreased REST expression and increased Cav2.2-α expression in CVP neurons from T2DM rats. REST shRNA also improved cardiac vagal function, measured by heart rate variability, and reduced the cumulative duration of MI-evoked ventricular arrhythmias in conscious rats. These data suggested that H2O2-REST signaling pathway could be a key factor to mediate cardiac vagal dysfunction and affect the occurrence of ventricular arrhythmias in T2DM. This study was supported by the NIH-NHLBI (R01HL144146 to YLL). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.