AUTHOR=Zhang Dongze , Tu Huiyin , Hu Wenfeng , Duan Bin , Zimmerman Matthew C. , Li Yu-Long 

TITLE=Hydrogen Peroxide Scavenging Restores N-Type Calcium Channels in Cardiac Vagal Postganglionic Neurons and Mitigates Myocardial Infarction-Evoked Ventricular Arrhythmias in Type 2 Diabetes Mellitus

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.871852

DOI=10.3389/fcvm.2022.871852

ISSN=2297-055X

ABSTRACT=<sec><title>Objective</title><p>Withdrawal of cardiac vagal activity is associated with ventricular arrhythmia-related high mortality in patients with type 2 diabetes mellitus (T2DM). Our recent study found that reduced cell excitability of cardiac vagal postganglionic (CVP) neurons is involved in cardiac vagal dysfunction and further exacerbates myocardial infarction (MI)-evoked ventricular arrhythmias and mortality in T2DM. However, the mechanisms responsible for T2DM-impaired cell excitability of CVP neurons remain unclear. This study tested if and how elevation of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) inactivates CVP neurons and contributes to cardiac vagal dysfunction and ventricular arrhythmogenesis in T2DM.</p></sec><sec><title>Methods and Results</title><p>Rat T2DM was induced by a high-fat diet plus streptozotocin injection. Local <italic>in vivo</italic> transfection of adenoviral catalase gene (Ad.CAT) successfully induced overexpression of catalase and subsequently reduced cytosolic H<sub>2</sub>O<sub>2</sub> levels in CVP neurons in T2DM rats. Ad.CAT restored protein expression and ion currents of N-type Ca<sup>2+</sup> channels and increased cell excitability of CVP neurons in T2DM. Ad.CAT normalized T2DM-impaired cardiac vagal activation, vagal control of ventricular function, and heterogeneity of ventricular electrical activity. Additionally, Ad.CAT not only reduced the susceptibility to ventricular arrhythmias, but also suppressed MI-evoked lethal ventricular arrhythmias such as VT/VF in T2DM.</p></sec><sec><title>Conclusions</title><p>We concluded that endogenous H<sub>2</sub>O<sub>2</sub> elevation inhibited protein expression and activation of N-type Ca<sup>2+</sup> channels and reduced cell excitability of CVP neurons, which further contributed to the withdrawal of cardiac vagal activity and ventricular arrhythmogenesis in T2DM. Our current study suggests that the H<sub>2</sub>O<sub>2</sub>-N-type Ca<sup>2+</sup> channel signaling axis might be an effective therapeutic target to suppress ventricular arrhythmias in T2DM patients with MI.</p></sec>