Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy
Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy
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DOI：
10.1016/j.jacc.2017.06.061
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发表时间：
2017-08-22
影响因子：
24
通讯作者：
Streckfuss-Boemeke, Katrin
中科院分区：
文献类型：
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作者：
Borchert, Thomas;Huebscher, Daniela;Streckfuss-Boemeke, Katrin
Takotsubo综合征（TTS）的特征是急性左心室功能障碍，并与急性期危及生命的并发症有关。TTS的发病机制尚不清楚。本研究的目的是建立TTS的体外诱导多能干细胞（iPSC）模型，以验证TTS iPSC-心肌细胞（CMs）中β-肾上腺素能信号改变的假设，并探讨遗传易感性是否是TTS病理生理学的基础。方法对TTS患者和对照组的体细胞进行重编程，iPSC并分化成CM。三个月大的CM进行儿茶酚胺刺激，以模拟神经体液过度刺激。结果在儿茶酚胺诱导的应激下，TTS-iPSC-CMs中增强的β-肾上腺素能信号增加了心脏应激标志物NR 4A 1的表达、环磷酸腺苷水平、心肌细胞的凋亡和心肌细胞的功能。和环腺苷一磷酸依赖性蛋白激酶A介导的RYR 2-S2808、PLN-S16、TNI-S23/24和Cav1.2-S1928的过度磷酸化，并导致钙瞬时50%衰变的时间减少。这些细胞的儿茶酚胺依赖性反应主要由TTS中的β 1-肾上腺素受体信号介导。与对照受试者相比，来自TTS-iPSC-CM的工程化心肌显示出收缩力受损和对异丙肾上腺素刺激的变力作用的更高敏感性。此外，在经儿茶酚胺处理的TTS-iPSC-CM中检测到改变的电活性和增加的脂质蓄积，并通过差异表达的脂质转运蛋白CD 36和CPT 1C证实。此外，我们发现在不同的关键监管机构的心脏function.CONCLUSIONS增强β-肾上腺素能信号和更高的敏感性，儿茶酚胺诱导的毒性被确定为与TTS表型相关的机制的遗传变异。国际Takotsubo登记研究[InterTAK登记研究] [InterTAK]; NCT 01947621）（C）2017作者。由爱思唯尔代表美国心脏病学会基金会出版。
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 b-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 beta-adrenergic signaling and TTS cardiomyocyte function.RESULTS Enhanced beta-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 beta(1)-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 beta-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) (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.