Dopamine D1/D5 Receptor Signaling Is Involved in Arrhythmogenesis in the Setting of Takotsubo Cardiomyopathy

Mengying Huang; Zhen Yang; Yingrui Li; Huan Lan; Lukas Cyganek; Goekhan Yuecel; Siegfried Lang; Karen Bieback; Ibrahim El-Battrawy; Xiaobo Zhou; Martin Borggrefe; Ibrahim Akin

doi:10.3389/fcvm.2021.777463

Dopamine D1/D5 Receptor Signaling Is Involved in Arrhythmogenesis in the Setting of Takotsubo Cardiomyopathy

Front Cardiovasc Med. 2022 Feb 4:8:777463. doi: 10.3389/fcvm.2021.777463. eCollection 2021.

Authors

Mengying Huang¹, Zhen Yang¹, Yingrui Li¹, Huan Lan², Lukas Cyganek^{3

4}, Goekhan Yuecel^{1

5

6}, Siegfried Lang^{1

5

6}, Karen Bieback⁷, Ibrahim El-Battrawy^{1

5

6}, Xiaobo Zhou^{1

2

5

6}, Martin Borggrefe^{1

5

6}, Ibrahim Akin^{1

5

6}

Affiliations

¹ First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany.
² Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
³ DZHK (German Center for Cardiovascular Research), Partner Site, Göttingen, Germany.
⁴ Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.
⁵ DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg, Germany.
⁶ DZHK (German Center for Cardiovascular Research), Partner Site, Mannheim, Germany.
⁷ Institute of Transfusion Medicine and Immunology, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany.

Abstract

Background: Previous studies suggested involvement of non-ß-adrenoceptors in the pathogenesis of Takotsubo cardiomyopathy (TTC). This study was designed to explore possible roles and underlying mechanisms of dopamine D1/D5 receptor coupled signaling in arrhythmogenesis of TTC.

Methods: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were challenged by toxic concentration of epinephrine (Epi, 0.5 mM for 1 h) for mimicking the catecholamine excess in setting of TTC. Specific receptor blockers and activators were used to unveil roles of D1/D5 receptors. Patch clamp, qPCR, and FACS analyses were performed in the study.

Results: High concentration Epi and two dopamine D1/D5 receptor agonists [(±)-SKF 38393 and fenoldopam] reduced the depolarization velocity and prolonged the duration of action potentials (APs) and caused arrhythmic events in iPSC-CMs, suggesting involvement of dopamine D1/D5 receptor signaling in arrhythmogenesis associated with QT interval prolongation in the setting of TTC. (±)-SKF 38393 and fenoldopam enhanced the reactive oxygen species (ROS)-production. H₂O₂ (100 μM) recapitulated the effects of (±)-SKF 38393 and fenoldopam on APs and a ROS-blocker N-acetylcysteine (NAC, 1 mM) abolished the effects, suggesting that the ROS-signaling is involved in the dopamine D1/D5 receptor actions. A NADPH oxidases blocker and a PKA- or PKC-blocker suppressed the effects of the dopamine receptor agonist, implying that PKA, NADPH oxidases and PKC participated in dopamine D1/D5 receptor signaling. The abnormal APs resulted from dopamine D1/D5 receptor activation-induced dysfunctions of ion channels including the Na⁺ and L-type Ca²⁺ and I_Kr channels.

Conclusions: Dopamine D1/D5 receptor signaling plays important roles for arrhythmogenesis of TTC. Dopamine D1/D5 receptor signaling in cardiomyocytes might be a potential target for treating arrhythmias in patients with TTC.

Keywords: D1/D5 dopamine receptor; Takotsubo cardiomyopathy; arrhythmia; catecholamine excess; human-induced pluripotent stem cell-derived cardiomyocytes.