Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy
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Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy. / Borchert, Thomas; Hübscher, Daniela; Guessoum, Celina I; Lam, Tuan-Dinh D; Ghadri, Jelena R; Schellinger, Isabel N; Tiburcy, Malte; Liaw, Norman Y; Li, Yun; Haas, Jan; Sossalla, Samuel; Huber, Mia A; Cyganek, Lukas; Jacobshagen, Claudius; Dressel, Ralf; Raaz, Uwe; Nikolaev, Viacheslav O; Guan, Kaomei; Thiele, Holger; Meder, Benjamin; Wollnik, Bernd; Zimmermann, Wolfram-Hubertus; Lüscher, Thomas F; Hasenfuss, Gerd; Templin, Christian; Streckfuss-Bömeke, Katrin.
in: J AM COLL CARDIOL, Jahrgang 70, Nr. 8, 22.08.2017, S. 975-991.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy
AU - Borchert, Thomas
AU - Hübscher, Daniela
AU - Guessoum, Celina I
AU - Lam, Tuan-Dinh D
AU - Ghadri, Jelena R
AU - Schellinger, Isabel N
AU - Tiburcy, Malte
AU - Liaw, Norman Y
AU - Li, Yun
AU - Haas, Jan
AU - Sossalla, Samuel
AU - Huber, Mia A
AU - Cyganek, Lukas
AU - Jacobshagen, Claudius
AU - Dressel, Ralf
AU - Raaz, Uwe
AU - Nikolaev, Viacheslav O
AU - Guan, Kaomei
AU - Thiele, Holger
AU - Meder, Benjamin
AU - Wollnik, Bernd
AU - Zimmermann, Wolfram-Hubertus
AU - Lüscher, Thomas F
AU - Hasenfuss, Gerd
AU - Templin, Christian
AU - Streckfuss-Bömeke, Katrin
N1 - Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2017/8/22
Y1 - 2017/8/22
N2 - BACKGROUND: Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis.OBJECTIVES: The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered β-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS.METHODS: Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated β-adrenergic signaling and TTS cardiomyocyte function.RESULTS: Enhanced β-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate-dependent protein kinase A-mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by β1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function.CONCLUSIONS: Enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621).
AB - BACKGROUND: Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis.OBJECTIVES: The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered β-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS.METHODS: Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated β-adrenergic signaling and TTS cardiomyocyte function.RESULTS: Enhanced β-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate-dependent protein kinase A-mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by β1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function.CONCLUSIONS: Enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621).
KW - Adult
KW - Catecholamines
KW - Cell Differentiation
KW - Cells, Cultured
KW - Female
KW - Humans
KW - Induced Pluripotent Stem Cells
KW - Middle Aged
KW - Myocytes, Cardiac
KW - Receptors, Adrenergic, beta
KW - Signal Transduction
KW - Takotsubo Cardiomyopathy
KW - Journal Article
U2 - 10.1016/j.jacc.2017.06.061
DO - 10.1016/j.jacc.2017.06.061
M3 - SCORING: Journal article
C2 - 28818208
VL - 70
SP - 975
EP - 991
JO - J AM COLL CARDIOL
JF - J AM COLL CARDIOL
SN - 0735-1097
IS - 8
ER -