Cardiac macrophages prevent sudden death during heart stress

Junichi Sugita, Katsuhito Fujiu (), Yukiteru Nakayama, Takumi Matsubara, Jun Matsuda, Tsukasa Oshima, Yuxiang Liu, Yujin Maru, Eriko Hasumi, Toshiya Kojima, Hiroshi Seno, Keisuke Asano, Ayumu Ishijima, Naoki Tomii, Masatoshi Yamazaki, Fujimi Kudo, Ichiro Sakuma, Ryozo Nagai, Ichiro Manabe () and Issei Komuro
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Junichi Sugita: Department of Cardiovascular Medicine, the University of Tokyo
Katsuhito Fujiu: Department of Cardiovascular Medicine, the University of Tokyo
Yukiteru Nakayama: Department of Cardiovascular Medicine, the University of Tokyo
Takumi Matsubara: Department of Cardiovascular Medicine, the University of Tokyo
Jun Matsuda: Department of Cardiovascular Medicine, the University of Tokyo
Tsukasa Oshima: Department of Cardiovascular Medicine, the University of Tokyo
Yuxiang Liu: Department of Cardiovascular Medicine, the University of Tokyo
Yujin Maru: Department of Cardiovascular Medicine, the University of Tokyo
Eriko Hasumi: Department of Cardiovascular Medicine, the University of Tokyo
Toshiya Kojima: Department of Cardiovascular Medicine, the University of Tokyo
Hiroshi Seno: The University of Tokyo
Keisuke Asano: The University of Tokyo
Ayumu Ishijima: The University of Tokyo
Naoki Tomii: The University of Tokyo
Masatoshi Yamazaki: The University of Tokyo
Fujimi Kudo: Chiba University
Ichiro Sakuma: The University of Tokyo
Ryozo Nagai: Jichi Medical University
Ichiro Manabe: Chiba University
Issei Komuro: Department of Cardiovascular Medicine, the University of Tokyo

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22178-0

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