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过氧化氢清除可恢复心脏迷走神经节后神经元中的N型钙通道，并减轻2型糖尿病中由心肌梗死诱发的室性心律失常。

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.

作者信息

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

机构信息

Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE, United States.

Mary and Dick Holland Regenerative Medicine Program, Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States.

出版信息

Front Cardiovasc Med. 2022 Apr 25;9:871852. doi: 10.3389/fcvm.2022.871852. eCollection 2022.

DOI:10.3389/fcvm.2022.871852
PMID:35548411
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9082497/
Abstract

OBJECTIVE: 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 (HO) inactivates CVP neurons and contributes to cardiac vagal dysfunction and ventricular arrhythmogenesis in T2DM. METHODS AND RESULTS: Rat T2DM was induced by a high-fat diet plus streptozotocin injection. Local transfection of adenoviral catalase gene (Ad.CAT) successfully induced overexpression of catalase and subsequently reduced cytosolic HO levels in CVP neurons in T2DM rats. Ad.CAT restored protein expression and ion currents of N-type Ca 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. CONCLUSIONS: We concluded that endogenous HO elevation inhibited protein expression and activation of N-type Ca 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 HO-N-type Ca channel signaling axis might be an effective therapeutic target to suppress ventricular arrhythmias in T2DM patients with MI.

摘要

目的：心脏迷走神经活动的减退与2型糖尿病（T2DM）患者室性心律失常相关的高死亡率有关。我们最近的研究发现，心脏迷走神经节后（CVP）神经元细胞兴奋性降低参与了心脏迷走神经功能障碍，并进一步加剧了T2DM患者心肌梗死（MI）诱发的室性心律失常和死亡率。然而，T2DM导致CVP神经元细胞兴奋性受损的机制仍不清楚。本研究测试了过氧化氢（HO）升高是否以及如何使CVP神经元失活，并导致T2DM患者心脏迷走神经功能障碍和室性心律失常的发生。 方法与结果：通过高脂饮食加链脲佐菌素注射诱导大鼠T2DM。局部转染腺病毒过氧化氢酶基因（Ad.CAT）成功诱导了过氧化氢酶的过表达，并随后降低了T2DM大鼠CVP神经元中的胞质HO水平。Ad.CAT恢复了T2DM大鼠CVP神经元中N型钙通道的蛋白表达和离子电流，并增加了其细胞兴奋性。Ad.CAT使T2DM受损的心脏迷走神经激活、迷走神经对心室功能的控制以及心室电活动的异质性恢复正常。此外，Ad.CAT不仅降低了室性心律失常的易感性，还抑制了T2DM大鼠MI诱发的致命性室性心律失常，如室性心动过速/心室颤动。 结论：我们得出结论，内源性HO升高抑制了N型钙通道的蛋白表达和激活，降低了CVP神经元的细胞兴奋性，这进一步导致了T2DM患者心脏迷走神经活动的减退和室性心律失常的发生。我们目前的研究表明，HO-N型钙通道信号轴可能是抑制MI的T2DM患者室性心律失常的有效治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ae/9082497/fb5e329d3a73/fcvm-09-871852-g0011.jpg
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Front Cardiovasc Med. 2022-4-25

[2]
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引用本文的文献

[1]
Hydrogen Peroxide-Induced Re-Expression of Repressor Element 1-Silencing Transcription Factor Contributes to Cardiac Vagal Dysfunction in Type 2 Diabetes Mellitus.

Antioxidants (Basel). 2025-5-14

[2]
Altered leptin signaling and attenuated cardiac vagal activity in rats with type 2 diabetes.

Front Physiol. 2025-2-26

[3]
Remodeling of the Intracardiac Ganglia During the Development of Cardiovascular Autonomic Dysfunction in Type 2 Diabetes: Molecular Mechanisms and Therapeutics.

Int J Mol Sci. 2024-11-20

本文引用的文献

[1]
Association between non-alcoholic fatty liver disease and impaired cardiac sympathetic/parasympathetic balance in subjects with and without type 2 diabetes-The Cooperative Health Research in South Tyrol (CHRIS)-NAFLD sub-study.

Nutr Metab Cardiovasc Dis. 2021-11-29

[2]
Reduced Cell Excitability of Cardiac Postganglionic Parasympathetic Neurons Correlates With Myocardial Infarction-Induced Fatal Ventricular Arrhythmias in Type 2 Diabetes Mellitus.

Front Neurosci. 2021-8-18

[3]
Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes.

Front Pharmacol. 2021-7-8

[4]
Molecular and Electrophysiological Role of Diabetes-Associated Circulating Inflammatory Factors in Cardiac Arrhythmia Remodeling in a Metabolic-Induced Model of Type 2 Diabetic Rat.

Int J Mol Sci. 2021-6-25

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Macrophage depletion in stellate ganglia alleviates cardiac sympathetic overactivation and ventricular arrhythmogenesis by attenuating neuroinflammation in heart failure.

Basic Res Cardiol. 2021-4-21

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Carvedilol improves heart rate variability indices, biomarkers but not cardiac nerve density in streptozotocin-induced T2DM model of diabetic cardiac autonomic neuropathy.

J Basic Clin Physiol Pharmacol. 2021-3-18

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Activation of the cardiac non-neuronal cholinergic system prevents the development of diabetes-associated cardiovascular complications.

Cardiovasc Diabetol. 2021-2-22

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Diabetes-induced changes in cardiac voltage-gated ion channels.

World J Diabetes. 2021-1-15

[9]
Short-Term Variability of the QT Interval Can be Used for the Prediction of Imminent Ventricular Arrhythmias in Patients With Primary Prophylactic Implantable Cardioverter Defibrillators.

J Am Heart Assoc. 2020-12

[10]
Is there cardiac autonomic neuropathy in prediabetes?

Auton Neurosci. 2020-12

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