Abstract
BackgroundPrevious 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.MethodsHuman-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.ResultsHigh 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 IKr channels.ConclusionsDopamine 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.
Highlights
Takotsubo cardiomyopathy (TTC) was initially described ∼25 years ago [1]
Our recent publications confirmed the successful differentiation of human-induced pluripotent stem cells (hiPSCs) into hiPSC-CMs by using qPCR, immunofluorescence and Fluorescence-Activated Cell Sorting (FACS) analysis regarding the expression of cardiac markers [26]
The results showed that Epi prolonged the duration of action potential at 10% repolarization (APD10) from 12.9 ± 0.40 to 14.55 ± 0.60 ms, the duration of action potential at 50% repolarization (APD50) from 210.86 ± 27.40 to 461.22 ± 68.22 ms and the duration of action potential duration at 90% repolarization (APD90) from 369.15 ± 36.58 to 667.98 ± 80.18 ms, respectively (Figures 2A–D)
Summary
Takotsubo cardiomyopathy (TTC) was initially described ∼25 years ago [1]. The most common symptoms of patients with TTC are chest pain and dyspnea. About 90% of patients with TTC are postmenopausal women who experience multiple stresses before the onset [3, 5]. Several possible causes have been proposed, such as catecholamine cardiotoxicity, metabolic disorders, coronary microvascular injury, multivessel epicardial coronary artery spasm and thyroidal dysfunction, the pathophysiology of TTC has not been fully established [6]. A commonly accepted hypothesis is the surge of catecholamines caused by intense psychological or physical stress [4, 7]. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
