The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency.
The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency.
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DOI：
10.1016/j.yjmcc.2023.04.005
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发表时间：
2023-04
影响因子：
5
通讯作者：
Kyungsoo Kim;Daniel J. Blackwell;Samantha L. Yuen;Madelaine P Thorpe;Jeff N Johnston;Răzvan L. Cornea;B. Knollmann
中科院分区：
文献类型：
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作者：
Kyungsoo Kim;Daniel J. Blackwell;Samantha L. Yuen;Madelaine P Thorpe;Jeff N Johnston;Răzvan L. Cornea;B. Knollmann
心房颤动（AF）是最常见的持续性心律失常，也是中风和发病的主要原因。人类房颤最强的遗传风险因素是染色体4 q25上的变异，靠近配对样同源框转录因子2基因PITX 2。尽管Pitx 2缺陷小鼠（Pitx 2 +/−）的房颤易感性增加，但其机制仍存在争议。最近的证据表明，Pitx 2缺乏时心脏ryanodine受体（RyR 2）过度活化，这可能与AF易感性有关。我们研究了起搏诱导的房颤易感性和Pitx 2单倍不足（+/−）小鼠和分离的心房肌细胞的自发性Ca 2+释放事件，以验证RyR 2过度活跃增加房颤易感性的假设，这可以通过有效的选择性RyR 2通道抑制剂ent-verticilide来预防。与同窝野生型Pitx 2 +/+相比，Pitx 2 +/−小鼠的透化和完整心房肌细胞中的Ca 2+火花和自发Ca 2+释放事件频率增加。心房短阵起搏持续增加Pitx 2 +/−小鼠的AF发生率和持续时间。RyR 2降冰片酯显著降低了完整心房肌细胞中自发性Ca 2+释放的频率，并降低了AF的易感性，降低了AF的发生率和持续时间。我们的数据表明，RyR 2活动过度通过异常的Ca 2+处理增强了Pitx 2 +/-小鼠SR Ca 2+渗漏和AF诱导能力。在房颤患者中，使用轮枝酯靶向治疗过度活跃的RyR 2可能是治疗Pitx 2缺陷引起的房性心律失常的一种可行的基于机制的方法。
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and morbidity. The strongest genetic risk factors for AF in humans are variants on chromosome 4q25, near the paired-like homeobox transcription factor 2 genePITX2. Although mice deficient in Pitx2 (Pitx2+/−) have increased AF susceptibility, the mechanism remains controversial. Recent evidence has implicated hyperactivation of the cardiac ryanodine receptor (RyR2) in Pitx2 deficiency, which may be associated with AF susceptibility. We investigated pacing-induced AF susceptibility and spontaneous Ca2+release events in Pitx2 haploinsufficient (+/−) mice and isolated atrial myocytes to test the hypothesis that hyperactivity of RyR2 increases susceptibility to AF, which can be prevented by a potent and selective RyR2 channel inhibitor,ent-verticilide. Compared with littermate wild-type Pitx2+/+, the frequency of Ca2+sparks and spontaneous Ca2+release events increased in permeabilized and intact atrial myocytes from Pitx2+/− mice. Atrial burst pacing consistently increased the incidence and duration of AF in Pitx2+/− mice. The RyR2 inhibitorent-verticilide significantly reduced the frequency of spontaneous Ca2+ release in intact atrial myocytes and attenuated AF susceptibility with reduced AF incidence and duration. Our data demonstrate that RyR2 hyperactivity enhances SR Ca2+leak and AF inducibility in Pitx2+/− mice via abnormal Ca2+handling. Therapeutic targeting of hyperactive RyR2 in AF usingent-verticilide may be a viable mechanism-based approach to treat atrial arrhythmias caused by Pitx2 deficiency.