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.
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.
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DOI：
10.3389/fcvm.2022.871852
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发表时间：
2022
影响因子：
3.6
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中科院分区：
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心脏迷走神经活动的减弱与 2 型糖尿病 (T2DM) 患者室性心律失常相关的高死亡率相关。我们最近的研究发现，心脏迷走神经节后（CVP）神经元的细胞兴奋性降低与心脏迷走神经功能障碍有关，并进一步加剧心肌梗死（MI）诱发的室性心律失常和 T2DM 患者的死亡率。然而，T2DM 损害 CVP 神经元细胞兴奋性的机制仍不清楚。本研究测试了过氧化氢 (H2O2) 的升高是否以及如何使 CVP 神经元失活并导致 T2DM 患者的心脏迷走神经功能障碍和室性心律失常发生。通过高脂饮食加链脲佐菌素注射诱导大鼠 T2DM。腺病毒过氧化氢酶基因 (Ad.CAT) 的局部体内转染成功诱导了 T2DM 大鼠 CVP 神经元过氧化氢酶的过度表达，并随后降低了胞质 H2O2 水平。 Ad.CAT 恢复了 T2DM 中 N 型 Ca2+ 通道的蛋白表达和离子电流，并增加了 CVP 神经元的细胞兴奋性。 Ad.CAT 使 T2DM 受损的心脏迷走神经激活、心室功能的迷走神经控制以及心室电活动的异质性正常化。此外，Ad.CAT 不仅降低了室性心律失常的易感性，而且还抑制了 MI 诱发的致命性室性心律失常，例如 T2DM 中的 VT/VF。我们得出的结论是，内源性 H2O2 升高抑制了 N 型 Ca2+ 通道的蛋白表达和激活，并降低了 CVP 神经元的细胞兴奋性，这进一步导致了 T2DM 中心脏迷走神经活动的减弱和室性心律失常的发生。我们目前的研究表明，H2O2-N 型 Ca2+ 通道信号轴可能是抑制 T2DM 合并 MI 患者室性心律失常的有效治疗靶点。
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 (H2O2) inactivates CVP neurons and contributes to cardiac vagal dysfunction and ventricular arrhythmogenesis in T2DM. Rat T2DM was induced by a high-fat diet plus streptozotocin injection. Local in vivo transfection of adenoviral catalase gene (Ad.CAT) successfully induced overexpression of catalase and subsequently reduced cytosolic H2O2 levels in CVP neurons in T2DM rats. Ad.CAT restored protein expression and ion currents of N-type Ca2+ 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. We concluded that endogenous H2O2 elevation inhibited protein expression and activation of N-type Ca2+ 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 H2O2-N-type Ca2+ channel signaling axis might be an effective therapeutic target to suppress ventricular arrhythmias in T2DM patients with MI.