Overproduction of reactive oxygen species in cardiac vagal postganglionic neurons contributes to myocardial infarction‐induced lethal ventricular arrhythmias in type 2 diabetes mellitus

Abstract

Myocardial infarction (MI)‐evoked ventricular arrhythmia is the major cause of mortality in type 2 diabetes mellitus (T2DM) patients. Although intensive glycemic control over time have been noted in T2DM patients, it fails to reduce MI‐related mortality in T2DM patients. Withdrawal of cardiac vagal (parasympathetic) activity is a common complication and is associated with arrhythmia‐related sudden cardiac death in T2DM patients. Our recent study found that T2DM‐reduced cell excitability of CVP neurons contributes to the withdrawal of cardiac vagal activity and further exacerbates acute MI‐evoked fatal ventricular arrhythmias and high mortality rate in T2DM. However, the mechanisms responsible for T2DM‐reduced cell excitability of CVP neurons are unclear. Since reactive oxygen species (ROS) has been reported to modulate calcium (Ca2+) channel activity in peripheral postganglionic neurons, here we tested if and how hydrogen peroxide (H2O2, a type of ROS) inactivates CVP neurons and subsequently contributes to MI‐evoked fatal ventricular arrhythmias in T2DM rats. Rat T2DM was induced by a high‐fat diet plus streptozotocin injection. Adenoviral catalase gene (Ad.CAT) or its vector control (Ad.Empty, 2 μl, 1x1010 pfu/ml) was microinjected into CVP neurons. Local in vivo transfection of Ad.CAT successfully induced overexpression of catalase and attenuated H2O2 overproduction in CVP neurons in T2DM rats. Additionally, transfection of Ad.CAT not only restored protein expression and ion currents of N‐type Ca2+ channels, but also increased cell excitability of CVP neurons in T2DM rats. Using Fluo3/AM with a confocal microscope, we also demonstrated that Ad.CAT gene transfection significantly restored intracellular Ca2+ levels in isolated CVP neurons from T2DM rats. Moreover, data from 24‐hour continuous ECG recording in conscious rats demonstrated that transfection of Ad.CAT into CVP neurons alleviated the heterogeneity of ventricular electrical activity (a critical factor of ventricular arrhythmogenesis). More importantly, Ad.CAT transfection into CVP neurons significantly reduced the cumulative duration of VT/VF induced by MI in conscious T2DM rats (28.3 ± 6.9 sec/hour in the T2DM+AD.CAT group vs. 71.7 ± 7.4 sec/hour in the T2DM group, P<0.05). Ad.Empty gene transfection into CVP neurons had no effects on intracellular H2O2 and Ca2+ levels, protein expression and ion currents of N‐type Ca2+ channels, cell excitability of CVP neurons, and duration of VT/VF induced by MI in T2DM rats. Based on these data, we concluded that overproduction of H2O2 decreased protein expression and activation of N‐type Ca2+ channels and reduced cell excitability of CVP neurons, which further contributed to ventricular arrhythmogenesis in T2DM. Our current study suggests that targeting H2O2‐N‐type Ca2+ channel signaling pathway in CVP neurons is an effective intervention against MI‐evoked fatal ventricular arrhythmias in the T2DM state.