biostudies-literatureUnknown8Huang MBundesministerium für Bildung und ForschungDeutsches Zentrum für Herz-Kreislaufforschung<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 <i>N</i>-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.<h4>Conclusions</h4>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.Frontiers in cardiovascular medicine777463https://www.ebi.ac.uk/biostudies/studies/S-EPMC8855058biostudies-literatureDopamine D1/D5 Receptor Signaling Is Involved in Arrhythmogenesis in the Setting of Takotsubo Cardiomyopathy.PMC8855058Yang ZLi YYuecel GBieback KHuang MAkin IEl-Battrawy ILang SCyganek LLan HZhou XBorggrefe MfalseDopamine D1/D5 Receptor Signaling Is Involved in Arrhythmogenesis in the Setting of Takotsubo Cardiomyopathy.<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 <i>N</i>-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.<h4>Conclusions</h4>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.2021-01-01T00:00:00Z20212024-11-09T22:29:57.87Z2024-11-09T22:29:57.87ZS-EPMC88550583518710210.3389/fcvm.2021.777463