NMDA-Type Glutamate Receptor Activation Promotes Ischemic Arrhythmias by Targeting the AKT1–TBX3–Nav1.5 Axis

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica Pub Date : 2025-08-22 DOI:10.1111/apha.70085

Yuxian He, Han Zhang, Qinggang Zhang, Zewei Sun, Xingang Sun, Ling Xia, Liangrong Zheng, Lihong Wang

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Abstract

Aim

The aim of this study is to determine the possible role of N-methyl-D-aspartate receptor (NMDAR) dysregulation in the ischemic electrical remodeling observed in patients with myocardial infarction (MI) and elucidate the underlying mechanisms.

Methods

Human heart tissue was obtained from the border of the infarct and remote zones of patients with ischemic heart disease, and mouse heart tissue was obtained from the peri-infarct zone. NMDAR expression was detected using immunofluorescence (IF) and Western blotting (WB). Spontaneous ventricular arrhythmias (VAs) in mice were detected using electrocardiogram backpacks. Electrical remodeling post-MI was detected using patch clamp recordings, quantitative real-time polymerase chain reactions, IF, and WB. Mechanistic studies were performed using bioinformatic analysis, plasmid and small interfering RNA transfection, lentiviral packaging, and site-directed mutagenesis.

Results

NMDAR is highly expressed in patients with ischemic heart disease and mice with MI. NMDAR inhibition reduces the occurrence of VAs. Mechanistically, NMDAR activation promotes electrophysiological remodeling, as characterized by decreased Nav1.5, Kv11.1, Kv4.2, Kv7.1, Kir2.1, and Cav1.2 expression in patients with ischemic heart disease and mice with MI and rescues these ion channels dysregulation in mice with MI to varying degrees by NMDAR inhibition. Decreased Nav1.5 expression and inward sodium current density were attenuated by NMDAR inhibition in primary rat cardiomyocytes. Moreover, NMDAR activation upregulates T-Box Transcription Factor 3 (TBX3) post-translationally, further downregulating Nav1.5 transcriptionally. Furthermore, AKT1 is the predominant isoform in the ventricular myocardium upstream of TBX3 and mediates NMDAR-induced TBX3 upregulation in cardiomyocytes.

Conclusion

NMDAR activation contributes to MI-induced VAs by regulating the AKT1–TBX3–Nav1.5 axis, providing novel therapeutic strategies for treating ischemic arrhythmias.

Abstract Image

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nmda型谷氨酸受体激活通过靶向AKT1-TBX3-Nav1.5轴促进缺血性心律失常

目的探讨n -甲基- d -天冬氨酸受体（NMDAR）失调在心肌梗死（MI）患者缺血性电重构中的可能作用，并阐明其机制。方法取材于缺血性心脏病患者梗死区边缘和远区，取材于梗死区周围，取材于小鼠心脏组织。采用免疫荧光（IF）和Western blotting （WB）检测NMDAR的表达。采用心电图包检测小鼠自发性室性心律失常（VAs）。使用膜片钳记录、定量实时聚合酶链反应、IF和WB检测心肌梗死后的电重构。机制研究采用生物信息学分析、质粒和小干扰RNA转染、慢病毒包装和定点诱变。结果NMDAR在缺血性心脏病患者和心肌梗死小鼠中高表达，抑制NMDAR可减少VAs的发生。在机制上，NMDAR激活促进电生理重构，其特征是缺血性心脏病患者和心肌梗死小鼠中Nav1.5、Kv11.1、Kv4.2、Kv7.1、Kir2.1和Cav1.2的表达降低，并通过NMDAR抑制不同程度地缓解心肌梗死小鼠这些离子通道失调。抑制NMDAR可降低大鼠心肌细胞内Nav1.5的表达和钠电流密度。此外，NMDAR激活可在翻译后上调T-Box转录因子3 (TBX3)，进一步下调Nav1.5的转录水平。此外，AKT1是TBX3上游心室心肌的主要亚型，并介导nmda诱导的TBX3在心肌细胞中的上调。结论NMDAR激活通过调节AKT1-TBX3-Nav1.5轴参与mi诱导的VAs，为缺血性心律失常的治疗提供了新的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Physiologica 医学-生理学

CiteScore

11.80

自引率

15.90%

发文量

182

审稿时长

4-8 weeks

期刊介绍： Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.