Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure

Toshihiro Yamaguchi; Tomokazu S Sumida; Seitaro Nomura; Masahiro Satoh; Tomoaki Higo; Masamichi Ito; Toshiyuki Ko; Kanna Fujita; Mary E Sweet; Atsushi Sanbe; Kenji Yoshimi; Ichiro Manabe; Toshikuni Sasaoka; Matthew R G Taylor; Haruhiro Toko; Eiki Takimoto; Atsuhiko T Naito; Issei Komuro

doi:10.1038/s41467-020-18128-x

Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure

Nat Commun. 2020 Aug 31;11(1):4364. doi: 10.1038/s41467-020-18128-x.

Authors

Toshihiro Yamaguchi^#¹, Tomokazu S Sumida^#^{1

2}, Seitaro Nomura^{1

3}, Masahiro Satoh^{3

4}, Tomoaki Higo⁵, Masamichi Ito¹, Toshiyuki Ko¹, Kanna Fujita¹, Mary E Sweet⁶, Atsushi Sanbe⁷, Kenji Yoshimi⁸, Ichiro Manabe⁹, Toshikuni Sasaoka¹⁰, Matthew R G Taylor^{6

11}, Haruhiro Toko^{1

12}, Eiki Takimoto¹, Atsuhiko T Naito¹³, Issei Komuro¹⁴

Affiliations

¹ Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.
³ Genome Science Division, Research Center for Advanced Science and Technologies, The University of Tokyo, Tokyo, Japan.
⁴ Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
⁵ Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
⁶ Human Medical Genetics and Genomics, University of Colorado, Boulder, CO, USA.
⁷ Department of Pharmacotherapeutics, School of Pharmacy, Iwate Medical University, Morioka, Japan.
⁸ Department of Neurophysiology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁹ Department of Disease Biology and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
¹⁰ Department of Comparative and Experimental Medicine, Brain Research Institute, Niigata University, Niigata, Japan.
¹¹ Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Boulder, CO, USA.
¹² Department of Advanced Translational Research and Medicine in Management of Pulmonary Hypertension, The University of Tokyo, Tokyo, Japan.
¹³ Department of Physiology, Faculty of Medicine, Toho University, Tokyo, Japan. [email protected].
¹⁴ Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [email protected].

^# Contributed equally.

Abstract

Pathophysiological roles of cardiac dopamine system remain unknown. Here, we show the role of dopamine D1 receptor (D1R)-expressing cardiomyocytes (CMs) in triggering heart failure-associated ventricular arrhythmia. Comprehensive single-cell resolution analysis identifies the presence of D1R-expressing CMs in both heart failure model mice and in heart failure patients with sustained ventricular tachycardia. Overexpression of D1R in CMs disturbs normal calcium handling while CM-specific deletion of D1R ameliorates heart failure-associated ventricular arrhythmia. Thus, cardiac D1R has the potential to become a therapeutic target for preventing heart failure-associated ventricular arrhythmia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arrhythmias, Cardiac / etiology*
Arrhythmias, Cardiac / prevention & control
Gene Expression Profiling / methods
Heart Failure*
Humans
Mice
Mice, Transgenic
Myocytes, Cardiac / metabolism*
Rats
Receptors, Dopamine D1 / genetics
Receptors, Dopamine D1 / metabolism*
Sequence Analysis, RNA / methods
Single-Cell Analysis / methods
Tachycardia, Ventricular / etiology
Tachycardia, Ventricular / prevention & control

Substances

DRD1 protein, human
Receptors, Dopamine D1