Cardiac macrophages prevent sudden death during heart stress

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

doi:10.1038/s41467-021-22178-0

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.

Highlights

Cardiac arrhythmias are a primary contributor to sudden cardiac death, a major unmet medical need
Given the sudden death phenotype and advanced AV block seen in clodronate-treated mice, these results strongly suggest that monocytes and macrophages are essential for survival during acute right ventricular (RV) pressure overload, presumably by suppressing severe arrhythmias
Intraperitoneal administration of Gap 19 to Areg−/− mice clearly reduced the incidence of isoproterenol-induced death (Supplementary Fig. 10). These results suggest that AREG is critically involved in the regulation of Cx43 localization and cardiac gap junction formation, possibly through Cx43 phosphorylation, and that Cx43 lateralization is a cause of life-threatening arrhythmias triggered by cardiac stress in Areg−/− mice

Summary

Introduction

Cardiac arrhythmias are a primary contributor to sudden cardiac death, a major unmet medical need. Deletion of Areg from macrophages led to disorganization of gap junctions and, in turn, lethal arrhythmias during acute stresses, including RV pressure overload and βadrenergic 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. We show that cardiac macrophages play an essential role in survival during cardiac stress by maintaining the cardiac electrical conduction through regulating cardiac gap junction formation These findings may pave the way for a new therapeutic method for sudden death

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Results

Conclusion