N. V. Bogert, M. Therre, S. Din, J. Furkel, X. Zhou, I. El-Battrawy, J. Heineke, P. A. Schweizer, I. Akin, H. A. Katus, N. Frey, F. Leuschner, M. H. Konstandin
{"title":"Macrophages enhance sodium channel expression in cardiomyocytes","authors":"N. V. Bogert, M. Therre, S. Din, J. Furkel, X. Zhou, I. El-Battrawy, J. Heineke, P. A. Schweizer, I. Akin, H. A. Katus, N. Frey, F. Leuschner, M. H. Konstandin","doi":"10.1007/s00395-024-01084-8","DOIUrl":null,"url":null,"abstract":"<p>Cardiac macrophages facilitate electrical conduction through the atrioventricular-node (AV) in mice. A possible role for cardiomyocyte-macrophage coupling on the effect of antiarrhythmic therapy has not been investigated yet. Holter monitoring was conducted in LysM<sup>Cre</sup>xCsf1r<sup>LsL−DTR</sup> mice (MM<sup>DTR</sup>) under baseline conditions and after an elctrophysiological stress test by flecainide. In vivo effects were recapitulated in vitro by patch-clamp experiments. The underlying mechanism was characterized by expression and localization analysis of connexin43 (Cx43) and voltage-gated-sodium-channel-5 (Na<sub>v</sub>1.5). ECG monitoring in MM<sup>DTR</sup> mice did not show any significant conduction abnormalities but a significantly attenuated flecainide-induced extension of RR- and PP-intervals. Patch-clamp analysis revealed that the application of flecainide to neonatal rat ventricular cardiomyocytes (CMs) changed their resting-membrane-potential (RMP) to more negative potentials and decreased action-potential-duration (APD50). Coupling of macrophages to CMs significantly enhances the effects of flecainide, with a further reduction of the RMP and APD50, mediated by an upregulation of Cx43 and Na<sub>v</sub>1.5 surface expression. Macrophage depletion in mice does not correlate with cardiac electric conduction delay. Cardiac macrophages amplify the effects of flecainide on electrophysiological properties of cardiomyocytes in vivo and in vitro<i>.</i> Mechanistically, formation of macrophage-cardiomyocyte cell–cell-contacts via Cx43 facilitates the recruitment of Na<sub>v</sub>1.5 to the cell membrane increasing flecainide effects.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5000,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Basic Research in Cardiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00395-024-01084-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Cardiac macrophages facilitate electrical conduction through the atrioventricular-node (AV) in mice. A possible role for cardiomyocyte-macrophage coupling on the effect of antiarrhythmic therapy has not been investigated yet. Holter monitoring was conducted in LysMCrexCsf1rLsL−DTR mice (MMDTR) under baseline conditions and after an elctrophysiological stress test by flecainide. In vivo effects were recapitulated in vitro by patch-clamp experiments. The underlying mechanism was characterized by expression and localization analysis of connexin43 (Cx43) and voltage-gated-sodium-channel-5 (Nav1.5). ECG monitoring in MMDTR mice did not show any significant conduction abnormalities but a significantly attenuated flecainide-induced extension of RR- and PP-intervals. Patch-clamp analysis revealed that the application of flecainide to neonatal rat ventricular cardiomyocytes (CMs) changed their resting-membrane-potential (RMP) to more negative potentials and decreased action-potential-duration (APD50). Coupling of macrophages to CMs significantly enhances the effects of flecainide, with a further reduction of the RMP and APD50, mediated by an upregulation of Cx43 and Nav1.5 surface expression. Macrophage depletion in mice does not correlate with cardiac electric conduction delay. Cardiac macrophages amplify the effects of flecainide on electrophysiological properties of cardiomyocytes in vivo and in vitro. Mechanistically, formation of macrophage-cardiomyocyte cell–cell-contacts via Cx43 facilitates the recruitment of Nav1.5 to the cell membrane increasing flecainide effects.
期刊介绍:
Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards.
Basic Research in Cardiology regularly receives articles from the fields of
- Molecular and Cellular Biology
- Biochemistry
- Biophysics
- Pharmacology
- Physiology and Pathology
- Clinical Cardiology