Macrophages enhance sodium channel expression in cardiomyocytes

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Basic Research in Cardiology Pub Date : 2024-10-09 DOI:10.1007/s00395-024-01084-8
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
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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.

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巨噬细胞增强心肌细胞中钠离子通道的表达
心脏巨噬细胞可促进小鼠房室结的电传导。心肌细胞-巨噬细胞耦合对抗心律失常治疗效果的可能作用尚未得到研究。在 LysMCrexCsf1rLsL-DTR 小鼠(MMDTR)的基线条件下和使用氟卡尼进行心电生理应激试验后,对其进行了 Holter 监测。通过膜片钳实验在体外重现了体内效应。通过对 connexin43(Cx43)和电压门控钠通道-5(Nav1.5)的表达和定位分析,确定了其基本机制。MMDTR 小鼠的心电图监测未显示任何明显的传导异常,但非卡尼诱导的 RR 和 PP 间期延长明显减弱。膜片钳分析显示,对新生大鼠心室心肌细胞(CMs)施用非卡尼会使其静息膜电位(RMP)变为更负的电位,并降低动作电位持续时间(APD50)。将巨噬细胞与 CMs 联用可显著增强非卡尼的作用,通过上调 Cx43 和 Nav1.5 的表面表达,进一步降低 RMP 和 APD50。小鼠巨噬细胞耗竭与心脏电传导延迟无关。在体内和体外,心脏巨噬细胞会放大非加尼对心肌细胞电生理特性的影响。从机理上讲,通过 Cx43 形成巨噬细胞-心肌细胞的细胞-细胞接触有助于将 Nav1.5 募集到细胞膜上,从而增强飞卡尼效应。
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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
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
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Investigating the cause of cardiovascular dysfunction in chronic kidney disease: capillary rarefaction and inflammation may contribute to detrimental cardiovascular outcomes The IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT): multicenter pig study on the effect of ischemic preconditioning CAESAR lives on with IMPACT: bringing rigor and relevance to cardioprotection research. Oxidative stress initiates hemodynamic change in CKD-induced heart disease. Macrophages enhance sodium channel expression in cardiomyocytes
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