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

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=8

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.777463

DOI=10.3389/fcvm.2021.777463

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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. H<sub>2</sub>O<sub>2</sub> (100 μM) recapitulated the effects of (±)-SKF 38393 and fenoldopam on APs and a ROS-blocker <italic>N</italic>-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<sup>+</sup> and L-type Ca<sup>2+</sup> and I<sub>Kr</sub> channels.</p></sec><sec><title>Conclusions</title><p>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.</p></sec>