Re‐expression of REST in ventricular vagal neurons aggravates myocardial infarctionevoked ventricular arrhythmia in type 2 diabetes mellitus

Abstract

Diabetes mellitus, especially type 2 diabetes mellitus (T2DM, 90 to 95% of diabetic population), is a major public health problem worldwide and has become a leading cause of mortality. Myocardial infarction (MI) is the most common cause of mortality in T2DM. Comparing with non‐diabetic patients, patients with T2DM are twice to die from MI. Withdrawal of cardiac vagal activity is considered to be an important trigger for MI‐induced ventricular arrhythmias in T2DM. Our previous study has demonstrated that N‐type Ca2+ currents and cell excitability of atrioventricular ganglion (AVG) neurons were reduced in T2DM rats. We have recently demonstrated that reduced expression of Cav2.2‐α in AVG neurons contributes to cardiac vagal dysfunction and ventricular arrhythmogenesis. The repressor element 1‐silencing transcription factor (REST) is a key factor to block Cav2.2‐α expression. Normally REST is not expressed in neuronal cells. Here, we test the hypothesis that re‐expression of REST inhibits N‐type Ca2+ channel function in AVG neurons and further reduces cardiac vagal activity and promotes MI‐evoked fatal ventricular arrhythmias in T2DM rats. Using reverse‐phase protein array, we found that there was no expression of REST in the AVG from sham rats, while REST expression was significantly increased in the AVG from T2DM rats. In vivo infection of lentiviral REST shRNA (2 μl, 1×107 TU/ml) to the AVG markedly reduced REST expression in the AVG from T2DM rats. REST shRNA also increased Cav2.2‐α expression in AVG neurons from T2DM rats. The results from whole‐cell patch clamp recording showed that REST shRNA markedly restored T2DM‐reduced N‐type Ca2+ currents and cell excitability in AVG neurons. Additionally, infection of REST shRNA to AVG neurons markedly restored cardiac vagal activity, as evidenced by blunted response of LVSP to left efferent vagal stimulation. Moreover, REST shRNA also decreased the inducibility of ventricular arrhythmia in anesthetized T2DM rats (0.67±0.6 in T2DM+REST group vs. 3.6±1.03 in T2DM group). The ECG data obtained from 24‐hour radiotelemetry recording in conscious rat demonstrated that REST shRNA significantly reduced the duration of MI‐evoked ventricular arrhythmia (39.39±13.03 sec/hour in T2DM+REST group vs. 64.26±13.17 sec/hour in T2DM group). Based on above data, we conclude that re‐expression of REST decreases Cav2.2‐α expression and N‐type Ca2+ currents in AVG neurons, and subsequently reduces cardiac vagal function and increases susceptibility to ventricular arrhythmias in the T2DM.Support or Funding InformationDHHS/NIH/NHLBI, 34‐5370‐2003‐001