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Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats: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<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>) inactivates CVP neurons and contributes to cardiac vagal dysfunction and ventricular arrhythmogenesis in T2DM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Rat T2DM was induced by a high-fat diet plus streptozotocin injection. Local <jats:italic>in vivo<\/jats:italic> transfection of adenoviral catalase gene (Ad.CAT) successfully induced overexpression of catalase and subsequently reduced cytosolic H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> levels in CVP neurons in T2DM rats. Ad.CAT restored protein expression and ion currents of N-type Ca<jats:sup>2+<\/jats: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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We concluded that endogenous H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> elevation inhibited protein expression and activation of N-type Ca<jats:sup>2+<\/jats: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<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-N-type Ca<jats:sup>2+<\/jats:sup> channel signaling axis might be an effective therapeutic target to suppress ventricular arrhythmias in T2DM patients with MI.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2022.871852","type":"journal-article","created":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T10:38:58Z","timestamp":1650883138000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"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"],"prefix":"10.3389","volume":"9","author":[{"given":"Dongze","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiyin","family":"Tu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenfeng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew 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