Journal Article

Cardiac macrophages prevent sudden death during heart stress

Liu, Yuxiang, Yamazaki, Masatoshi, Maru, Yujin, Matsubara, Takumi, Matsuda, Jun, Nagai, Ryozo, Asano, Keisuke, Kudo, Fujimi, Komuro, Issei, Sakuma, Ichiro, Seno, Hiroshi, Hasumi, Eriko, Kojima, Toshiya, Manabe, Ichiro, Nakayama, Yukiteru, Ishijima, Ayumu, Tomii, Naoki, Fujiu, Katsuhito, Oshima, Tsukasa, Sugita, Junichi

2021

Overview

Cardiac arrhythmias are a primary contributor to sudden cardiac death, a major unmet medical need. Because right ventricular (RV) dysfunction increases the risk for sudden cardiac death, we examined responses to RV stress in mice. Among immune cells accumulated in the RV after pressure overload-induced by pulmonary artery banding, interfering with macrophages caused sudden death from severe arrhythmias. We show that cardiac macrophages crucially maintain cardiac impulse conduction by facilitating myocardial intercellular communication through gap junctions. Amphiregulin (AREG) produced by cardiac macrophages is a key mediator that controls connexin 43 phosphorylation and translocation in cardiomyocytes. Deletion of Areg from macrophages led to disorganization of gap junctions and, in turn, lethal arrhythmias during acute stresses, including RV pressure overload and β-adrenergic receptor stimulation. These results suggest that AREG from cardiac resident macrophages is a critical regulator of cardiac impulse conduction and may be a useful therapeutic target for the prevention of sudden death. Cardiac immune cells play various roles in the maintenance of homeostasis and diseases in the heart. Here the authors show that cardiac resident macrophages are a critical regulator of cardiac impulse conduction through amphiregulin production, contributing to the prevention of sudden death.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 13/51 / 631/250/2504/342 / 692/4019/592/75/230 / 692/4019/592/75/29 / 9/25 / Adrenergic receptors / Amphiregulin / Amphiregulin - metabolism / Amphiregulin - physiology / Animals / Animals, Newborn / Arrhythmias, Cardiac - complications / Cardiac arrhythmia / Cardiomyocytes / Cell death / Cell signaling / Cells, Cultured / Conduction / Connexin 43 / Coronary artery disease / Death / Death, Sudden, Cardiac - etiology / Death, Sudden, Cardiac - prevention & control / Defibrillators / Female / Gap junctions / Gap Junctions - physiology / Heart diseases / HeLa Cells / Homeostasis / Humanities and Social Sciences / Humans / Immune system / Macrophages / Macrophages - metabolism / Macrophages - physiology / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Mortality / multidisciplinary / Myocardium - cytology / Myocardium - metabolism / Myocytes, Cardiac - cytology / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - physiology / Overloading / Phosphorylation / Prevention / Pulmonary arteries / Pulmonary artery / Receptors (physiology) / Receptors, Adrenergic, beta - metabolism / Science / Science (multidisciplinary) / Therapeutic targets / Translocation / Ventricle