Catecholamine-Dependent ß-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy.
J Am Coll Cardiol
; 70(8): 975-991, 2017 Aug 22.
Article
em En
| MEDLINE
| ID: mdl-28818208
ABSTRACT
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 ß-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 ß-adrenergic signaling and TTS cardiomyocyte function.RESULTS:
Enhanced ß-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 ß1-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 ß-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).Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Catecolaminas
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Receptores Adrenérgicos beta
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Cardiomiopatia de Takotsubo
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Células-Tronco Pluripotentes Induzidas
Limite:
Adult
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Female
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Humans
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Middle aged
Idioma:
En
Revista:
J Am Coll Cardiol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Alemanha