Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression
Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression
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DOI：
10.1126/scitranslmed.aan0724
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发表时间：
2018-09-12
影响因子：
17.1
通讯作者：
Toischer, Karl
中科院分区：
文献类型：
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作者：
Mohamed, Belal A.;Hartmann, Nico;Toischer, Karl
通过心脏兰尼碱受体 (RyR2) 增加肌浆网 (SR) Ca2+ 渗漏被认为在心力衰竭 (HF) 和心律失常的发展中发挥机制作用。使用选择性 RyR2 稳定剂 rycal S36 治疗的小鼠，在压力超负荷 (PO) 和心肌梗塞 (MI) 模型中表现出 SR Ca2+ 渗漏正常化并提高了生存率。通过超声心动图和分子标记测量发现，rycal S36 治疗的小鼠与安慰剂治疗的小鼠相比，心力衰竭的发生没有差异。通过与 rycal 无关的 RyR2 稳定剂丹曲林减少 PO 模型中的 SR Ca2+ 渗漏，并不能减缓心力衰竭的进展。心力衰竭的发生并未因容量超载中 RyR2 突变 (R2474S) 导致 SR Ca2+ 渗漏增加而加剧，这是一种 SR Ca2+ 渗漏独立的心力衰竭模型。在 PO 和 MI 小鼠体内和离体 Langendorff 灌注心脏中，通过 rycal S36 治疗可减少心律失常发作。与安慰剂细胞相比，来自小鼠衰竭心脏、人心室衰竭和心房非衰竭心肌的分离心肌细胞显示延迟后除极、自发和诱导的 Ca2+ 波以及 rycal S36 的触发活动减少，而 Ca2+ 瞬态、SR Ca2+ 负荷、SR Ca2+ 三磷酸腺苷酶功能和动作电位持续时间不受影响。 Rycal S36 对从儿茶酚胺能多形性室性心动过速患者分离的人诱导多能干细胞进行治疗可以挽救渗漏的 RyR2 受体。这些结果表明，SR Ca2+ 渗漏并不主要影响收缩性心力衰竭的进展，而 rycal S36 治疗可显着减少室性心律失常，从而提高小鼠的生存率。
Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca2+ leak and improved survival in pressure overload (PO) and myocardial infarction (MI) models. The development of HF, measured by echocardiography and molecular markers, showed no difference in rycal S36-versus placebo-treated mice. Reduction of SR Ca2+ leak in the PO model by the rycal-unrelated RyR2 stabilizer dantrolene did not mitigate HF progression. Development of HF was not aggravated by increased SR Ca2+ leak due to RyR2 mutation (R2474S) in volume overload, an SR Ca2+ leakindependent HF model. Arrhythmia episodes were reduced by rycal S36 treatment in PO and MI mice in vivo and ex vivo in Langendorff-perfused hearts. Isolated cardiomyocytes from murine failing hearts and human ventricular failing and atrial nonfailing myocardium showed reductions in delayed afterdepolarizations, in spontaneous and induced Ca2+ waves, and in triggered activity in rycal S36 versus placebo cells, whereas the Ca2+ transient, SR Ca2+ load, SR Ca2+ adenosine triphosphatase function, and action potential duration were not affected. Rycal S36 treatment of human induced pluripotent stem cells isolated from a patient with catecholaminergic polymorphic ventricular tachycardia could rescue the leaky RyR2 receptor. These results suggest that SR Ca2+ leak does not primarily influence contractile HF progression, whereas rycal S36 treatment markedly reduces ventricular arrhythmias, thereby improving survival in mice.