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Transcription factor Meis1 act as a new regulator of ischemic arrhythmias in mice.

التفاصيل البيبلوغرافية
العنوان: Transcription factor Meis1 act as a new regulator of ischemic arrhythmias in mice.
المؤلفون: Liu Y; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Li J; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Xu N; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Yu H; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Gong L; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Li Q; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Yang Z; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Li S; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Yang J; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Huang D; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Xue Y; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Xue G; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Liu J; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Chen H; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Zhang R; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Li A; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Zhao Y; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Li P; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Li M; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Liu M; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China., Wang N; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China. Electronic address: wangning@ems.hrbmu.edu.cn., Cai B; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University (Institute of Clinical Pharmacy, The University Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions), Harbin, China. Electronic address: caibz@ems.hrbmu.edu.cn.
المصدر: Journal of advanced research [J Adv Res] 2022 Jul; Vol. 39, pp. 275-289. Date of Electronic Publication: 2021 Nov 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cairo University, production and hosting by Elsevier B. V Country of Publication: Egypt NLM ID: 101546952 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2090-1224 (Electronic) Linking ISSN: 20901224 NLM ISO Abbreviation: J Adv Res Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Giza, Egypt] : Cairo University, production and hosting by Elsevier B. V.
مواضيع طبية MeSH: Myeloid Ecotropic Viral Integration Site 1 Protein*/genetics , Myeloid Ecotropic Viral Integration Site 1 Protein*/metabolism , Myocardial Infarction*/metabolism , Transcription Factors*/metabolism, Animals ; Arrhythmias, Cardiac ; Death, Sudden, Cardiac ; Mice ; Mice, Inbred C57BL ; Myocytes, Cardiac/metabolism
مستخلص: Introduction: The principal voltage-gated Na + channel, Na V 1.5 governs heart excitability and conduction. Na V 1.5 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.
Objectives: Here we aimed to study whether Meis1 could act as a key regulator to mediate cardiac Na + channel and its underlying mechanisms.
Methods: 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 I Na 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 Na V 1.5 in each group.
Results: 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 I Na current density and Na V 1.5 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 Na V 1.5 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.
Conclusion: 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 Na V 1.5 dysregulation in infarcted heart, and provides new therapeutic strategies for malignant arrhythmias and sudden cardiac death following MI.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022. Production and hosting by Elsevier B.V.)
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فهرسة مساهمة: Keywords: CDC20; Meis1; Myocardial infarction; Na(V)1.5 channel; Ubiquitin; Ventricular arrhythmias
المشرفين على المادة: 0 (Meis1 protein, mouse)
0 (Myeloid Ecotropic Viral Integration Site 1 Protein)
0 (Transcription Factors)
تواريخ الأحداث: Date Created: 20220701 Date Completed: 20220707 Latest Revision: 20220716
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC9263651
DOI: 10.1016/j.jare.2021.11.004
PMID: 35777912
قاعدة البيانات: MEDLINE
الوصف
تدمد:2090-1224
DOI:10.1016/j.jare.2021.11.004