Transcription Factor Meis1 Act As a New Regulator Of Ischemic Arrhythmias In Mice

Background: The principal voltage-gated Nam+ channel, NaV1.5 governs heart excitability and conduction. NaV1.5 dysregulation is responsible for ventricular arrhythmias and subsequent sudden cardiac death in post-infarct hearts. The transcription factor Meis1 plays an important 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 set out to study whether Meis1 could act as a key regulator to mediate cardiac Na+ channels and arrhythmogenesis and its underlying mechanisms. Methods: Heart-specific Meis1 overexpression was established by AAV9 virus injection in C57BL/6 mice. The QTc interval, 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 used to study the I Na characteristics of isolated mouse ventricular myocytes. Findings: We found that forced expression of Meis1 rescued the prolongation of heart rate corrected QT (QTc) interval, produced anti-arrhythmic activity and improved epicardial conduction velocity in infarcted mouse hearts. Mechanistically, Meis1 may ameliorate cardiac electrophysiological remodeling as characterized by the decrease of INa current density and NaV1.5 expression in marginal zone of infarcted mouse hearts. Furthermore, in vitro studies showed that E3 ubiquitin ligase CDC20 led to the ubiquitination and degradation of Meis1, which blocked the transcriptional regulation of SCN5A. Interpretation: This study demonstrates that Meis1 overexpression can effectively inhibit the ventricular arrhythmia by regulating the transcription of SCN5A and cardiac electrical conductance in mouse ischemic heart, which provides new therapeutic strategies for malignant arrhythmias and sudden cardiac death following MI. Funding: This work was supported by the National Nature Science Foundation of China [Grant No. 81573425 and 81773733 to NW]. Declaration of Interest: None to declare. Ethical Approval: All animal experiments were performed along with the NIH guidelines (Guide for the care and use of laboratory animals, NIH Publication No. 85-23, revised 1996) and were conducted in accordance with the protocols approved by the Institutional Animal Care and Use Committee of Harbin Medical University.