Transcription factor Meis1 act as a new regulator of ischemic arrhythmias in mice.
Transcription factor Meis1 act as a new regulator of ischemic arrhythmias in mice.
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转录因子 Meis1 作为小鼠缺血性心律失常的新调节因子。
DOI：
10.1016/j.jare.2021.11.004
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发表时间：
2022-07
影响因子：
10.7
通讯作者：
Cai, Benzhi
中科院分区：
文献类型：
--
作者：
Liu, Yining;Li, Jiamin;Xu, Ning;Yu, Hang;Gong, Liling;Li, Qingsui;Yang, Zhenyu;Li, Sijia;Yang, Jiming;Huang, Di;Xue, Yadong;Xue, Genlong;Liu, Jiali;Chen, Haixin;Zhang, Ruijie;Li, Anqi;Zhao, Yiming;Li, PengYu;Li, Ming;Liu, Mingbin;Wang, Ning;Cai, Benzhi
心肌梗死后Meis1的降低导致对心律失常的易感性增加。Meis1缺陷与CDC20介导的泛素化蛋白酶体途径有关。Meis1在心肌细胞中作为SCN5A的一种新的转录激活因子。Meis1恢复后，心肌细胞电生理功能得到改善。Meis1是治疗心肌梗死后心律失常的新靶点。主电压门控Na+通道NaV1.5控制心脏兴奋性和传导。在梗死后心脏中，NaV1.5失调是室性心律失常和随后的心源性猝死（SCD）的原因。转录因子Meis1在决定心肌细胞的分化命运和再生能力中起着重要作用。然而，Meis1在心肌梗死（MI）后缺血性心律失常中的功能仍未明确。在此，我们旨在研究Meis1是否可以作为介导心脏Na+通道的关键调节因子及其潜在机制。通过AAV9病毒注射C57BL/6小鼠，建立了心脏特异性Meis1过表达。分别采用心电图、程控电刺激和光学测图技术评价QRS持续时间、室性心律失常发生率和心传导速度。采用膜片钳法观察小鼠离体心室肌细胞的INa特征。在体外，Meis1在缺氧处理的新生儿心肌细胞中也过表达。采用免疫印迹法和免疫荧光法检测各组中NaV1.5的表达变化。我们发现，Meis1的强制表达挽救了QRS复合物的延长，产生抗心律失常活性，提高了梗死小鼠心脏的心外膜传导速度。从机制上看，Meis1的恢复可以改善心肌梗死小鼠的心脏电生理变化，其特征是恢复心肌梗死小鼠心脏边缘区心肌细胞的INa电流密度和NaV1.5表达水平。此外，体外研究表明，Meis1还能挽救缺氧诱导的心室肌细胞中NaV1.5的表达下降和功能障碍。我们进一步发现E3泛素连接酶CDC20可导致Meis1的泛素化和降解，从而阻断Meis1对SCN5A的转录调控，最终导致缺血-缺氧心肌细胞的电生理重构。CDC20介导Meis1的泛素化，调控小鼠心肌细胞SCN5A的转录和心脏电传导。这一发现揭示了心肌梗死中NaV1.5异常的新机制，为心肌梗死后恶性心律失常和心源性猝死的治疗提供了新的策略。
The reduction of Meis1 after MI leads to an increased susceptibility to arrhythmia. Meis1 deficiency is related to ubiquitination proteasome pathway mediated by CDC20. Meis1 acts as a new transcription activator for SCN5A in cardiomyocytes. After Meis1 recovery, the electrophysiological function in cardiomyocytes are improved. Meis1 is a new target for the treatment of arrhythmia after myocardial infarction. The principal voltage-gated Na+ channel, NaV1.5 governs heart excitability and conduction. NaV1.5 dysregulation is responsible for ventricular arrhythmias and subsequent sudden cardiac death (SCD) in post-infarct hearts. The transcription factor Meis1 performs a significant role in determining differentiation fate and regenerative capability of cardiomyocytes. However, the functions of Meis1 in ischemic arrhythmias following myocardial infarction (MI) are still largely undefined. Here we aimed to study whether Meis1 could act as a key regulator to mediate cardiac Na+ channel and its underlying mechanisms. Heart-specific Meis1 overexpression was established by AAV9 virus injection in C57BL/6 mice. The QRS duration, the incidence of ventricular arrhythmias and cardiac conduction velocity were evaluated by ECG, programmed electrical stimulation and optical mapping techniques respectively. The conventional patch clamp technique was performed to explore the INa characteristics of isolated mouse ventricular myocytes. In vitro, Meis1 was also overexpressed in hypoxic-treated neonatal cardiomyocytes. The analysis of immunoblotting and immunofluorescence were used to detect the changes in the expression of NaV1.5 in each group. We found that forced expression of Meis1 rescued the prolongation of QRS complex, produced anti-arrhythmic activity and improved epicardial conduction velocity in infarcted mouse hearts. In terms of mechanisms, cardiac electrophysiological changes of MI mice can be ameliorated by the recovery of Meis1, which is characterized by the restoration of INa current density and NaV1.5 expression level of cardiomyocytes in the marginal zone of MI mouse hearts. Furthermore, in vitro studies showed that Meis1 was also able to rescue hypoxia-induced decreased expression and dysfunction of NaV1.5 in ventricular myocytes. We further revealed that E3 ubiquitin ligase CDC20 led to the ubiquitination and degradation of Meis1, which blocked the transcriptional regulation of SCN5A by Meis1 and ultimately led to the electrophysiological remodeling in ischemic-hypoxic cardiomyocytes. CDC20 mediates ubiquitination of Meis1 to govern the transcription of SCN5A and cardiac electrical conduction in mouse cardiomyocytes. This finding uncovers a new mechanism of NaV1.5 dysregulation in infarcted heart, and provides new therapeutic strategies for malignant arrhythmias and sudden cardiac death following MI.
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影响因子：
3
作者：
Gholamzadeh A;Amini S;Mohammadpour AH;Vahabzadeh M;Fazelifar AF;Fazlinezhad A;Dehghani M;Moohebati M;Dastani M;Malaekeh-Nikouie B;Falsoleiman H
通讯作者：
Falsoleiman H
影响因子：
10.8
作者：
Aimond, F;Alvarez, JL;Vassort, G
通讯作者：
Vassort, G
影响因子：
5.5
作者：
Hu, Dan;Viskin, Sami;Antzelevitch, Chares
通讯作者：
Antzelevitch, Chares
影响因子：
37.8
作者：
Baba, S;Dun, W;Boyden, PA
通讯作者：
Boyden, PA
影响因子：
7.7
作者：
Bouilloux, Fabrice;Thireau, Jerome;Marmigere, Frederic
通讯作者：
Marmigere, Frederic