Suppression of Arrhythmia by Enhancing Mitochondrial Ca(2+) Uptake in Catecholaminergic Ventricular Tachycardia Models.
Suppression of Arrhythmia by Enhancing Mitochondrial Ca(2+) Uptake in Catecholaminergic Ventricular Tachycardia Models.
复制标题
通过增强Catecholamin能室中心动过速模型中的线粒体Ca（2+）摄取来抑制心律不齐。
DOI：
10.1016/j.jacbts.2017.06.008
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发表时间：
2017-12
期刊：
影响因子：
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通讯作者：
Schredelseker J
中科院分区：
文献类型：
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作者：
Schweitzer MK;Wilting F;Sedej S;Dreizehnter L;Dupper NJ;Tian Q;Moretti A;My I;Kwon O;Priori SG;Laugwitz KL;Storch U;Lipp P;Breit A;Mederos Y Schnitzler M;Gudermann T;Schredelseker J
在心肌细胞中，Ca 2+从肌浆网到线粒体的快速转移可以通过靶向VDAC 2的MiCUPS efsevin和靶向MCU的山奈酚来增强。用MiCUPS增强肌浆网到线粒体的Ca 2+转移抑制CPVT小鼠模型心肌细胞中的促钙离子生成性Ca 2+事件和自发性动作电位。用MiCUPS体内治疗CPVT小鼠减少肾上腺素能刺激后的室性心动过速发作。在来自CPVT患者的诱导多能干细胞衍生的心肌细胞中，两种MiCUP都减少了致炎性Ca 2+事件。我们的数据建立快速线粒体Ca 2+摄取作为一个有前途的候选结构的药物治疗人类心律失常。心血管疾病相关的死亡通常由心律失常引起，但由于常用抗心律失常药物的危险副作用，治疗选择有限。心脏节律性强烈依赖于心肌细胞Ca 2+处理，并且流行的心脏疾病与细胞内Ca 2+处理的扰动有因果关系。因此，细胞内Ca 2+转运蛋白是新的和更安全的抗肿瘤治疗的主要候选结构。线粒体和线粒体Ca ~（2+）转运蛋白是心脏Ca ~（2+）处理的重要调节因子。在此，作者评价了药物激活线粒体Ca 2+摄取治疗心律失常的潜力。为此，作者在体外和体内以及来自CPVT患者的诱导多能干细胞衍生的心肌细胞中，检测了增强线粒体Ca 2+摄取的物质在ryanodine受体2（RyR 2）介导的儿茶酚胺能多态性室性心动过速（CPVT）小鼠模型中抑制心律失常的能力。在RyR 2 R4496 C/WT小鼠新鲜分离的心肌细胞中，efsevin是线粒体外膜中电压依赖性阴离子通道2（VDAC 2）的合成激动剂，可阻止舒张期Ca 2+波和自发动作电位的形成。通过阻断线粒体钙单向转运体（MCU），efsevin的抗肿瘤作用被取消，但可以使用天然MCU激活剂山奈酚复制。线粒体Ca 2+摄取增强剂（MiCUPS）efsevin和山奈酚在体内显著减少RyR 2 R4496 C/WT小鼠中应激诱导的室性心动过速的发作，并且在人iPSC衍生的心肌细胞中消除舒张期促心律失常Ca 2+事件。这些结果强调了增强线粒体Ca 2+摄取以抑制CPVT实验模型中的致瘤事件的直接潜力，并将MiCUP确立为治疗和预防Ca 2+触发的心律失常（如CPVT）的有前景的药理学工具。
Fast transfer of Ca2+ from the sarcoplasmic reticulum into mitochondria in cardiomyocytes can be enhanced by the MiCUps efsevin, targeting the VDAC2, and kaempferol, targeting the MCU. Enhancing sarcoplasmic reticulum-to-mitochondria Ca2+ transfer with MiCUps suppresses arrhythmogenic Ca2+ events and spontaneous action potentials in cardiomyocytes from a mouse model of CPVT. In vivo treatment of CPVT mice with MiCUps reduces episodes of ventricular tachycardia after adrenergic stimulation. In induced pluripotent stem cell-derived cardiomyocytes from a CPVT patient, both MiCUps reduce arrhythmogenic Ca2+ events. Our data establish fast mitochondrial Ca2+ uptake as a promising candidate structure for pharmacological treatment of human cardiac arrhythmia. Cardiovascular disease-related deaths frequently arise from arrhythmias, but treatment options are limited due to perilous side effects of commonly used antiarrhythmic drugs. Cardiac rhythmicity strongly depends on cardiomyocyte Ca2+ handling and prevalent cardiac diseases are causally associated with perturbations in intracellular Ca2+ handling. Therefore, intracellular Ca2+ transporters are lead candidate structures for novel and safer antiarrhythmic therapies. Mitochondria and mitochondrial Ca2+ transport proteins are important regulators of cardiac Ca2+ handling. Here, the authors evaluated the potential of pharmacological activation of mitochondrial Ca2+ uptake for the treatment of cardiac arrhythmia. To this aim, the authors tested substances that enhance mitochondrial Ca2+ uptake for their ability to suppress arrhythmia in a murine model for ryanodine receptor 2 (RyR2)-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT) in vitro and in vivo and in induced pluripotent stem cell-derived cardiomyocytes from a CPVT patient. In freshly isolated cardiomyocytes of RyR2R4496C/WT mice efsevin, a synthetic agonist of the voltage-dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane, prevented the formation of diastolic Ca2+ waves and spontaneous action potentials. The antiarrhythmic effect of efsevin was abolished by blockade of the mitochondrial Ca2+ uniporter (MCU), but could be reproduced using the natural MCU activator kaempferol. Both mitochondrial Ca2+ uptake enhancers (MiCUps), efsevin and kaempferol, significantly reduced episodes of stress-induced ventricular tachycardia in RyR2R4496C/WT mice in vivo and abolished diastolic, arrhythmogenic Ca2+ events in human iPSC-derived cardiomyocytes. These results highlight an immediate potential of enhanced mitochondrial Ca2+ uptake to suppress arrhythmogenic events in experimental models of CPVT and establish MiCUps as promising pharmacological tools for the treatment and prevention of Ca2+-triggered arrhythmias such as CPVT.