Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts.
Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts.
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DOI：
10.1042/bcj20160606
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发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Chen SR
中科院分区：
文献类型：
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作者：
Zhong X;Sun B;Vallmitjana A;Mi T;Guo W;Ni M;Wang R;Guo A;Duff HJ;Gillis AM;Song LS;Hove-Madsen L;Benitez R;Chen SR
胞浆内钙瞬变（Ca 2+ alternans）振幅的搏动-搏动交替被认为是心脏交替的主要原因，心脏交替可导致心律失常和猝死。尽管其在乳腺癌发生中起重要作用，但其机制仍不清楚.在此，我们研究了心脏ryanodine受体（RyR 2）的作用，主要的Ca 2+释放通道负责胞浆Ca 2+瞬变，在心脏交替。我们使用一个独特的小鼠模型，携带一个功能抑制（SOF）RyR 2突变（E4872 Q），我们评估了遗传抑制RyR 2功能的影响钙和动作电位时程（APD）交替在完整的心脏，和心电图（ECG）交替在体内。我们发现RyR 2-SOF心脏表现出延长的肌浆网Ca 2+释放不应性和增强的Ca 2+交替倾向。RyR 2-SOF心脏/小鼠还表现出APD和ECG交替的倾向增加。咖啡因可增强RyR 2活性和儿茶酚胺能多形性室性心动过速（CPVT）的倾向，抑制RyR 2-SOF心脏中的Ca 2+交替，而卡维地洛（一种抑制RyR 2活性和CPVT的β受体阻滞剂）可促进这些心脏中的Ca 2+交替。因此，RyR 2功能是Ca 2+、APD和ECG交替的重要决定因素。我们的数据还表明，RyR 2的活性以相反的方式影响心脏交替和CPVT的倾向。因此，过度抑制或增强RyR 2功能是促排卵的。
Beat-to-beat alternations in the amplitude of the cytosolic Ca2+ transient (Ca 2+ alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca 2+ alternans remains poorly understood. Here we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca2+ release channel responsible forcytosolic Ca2+ transients, in cardiac alternans. Using a unique mouse model harboring a suppression -of-function (SOF) RyR2 mutation (E4872Q), we assessed the effect of genetically suppressing RyR2 function on Ca 2+ and action potential duration (APD)alternans in intact hearts , and electrocardiogram (ECG) alternans in vivo. We found that RyR2-SOF hearts displayed prolonged sarcoplasmic reticulum Ca2+ release refractoriness and enhanced propensity for Ca2+ al ternans. RyR2-SOF hearts/mice also exhibited increased propensity for APD and ECG alternans. Caffeine, which enhances RyR2 activity and the propensity for catecholaminergic polymorphic ventricular tachycardia ( CPVT), suppressed Ca2+ alternans in RyR2 -SOF hearts, whereas carvedilol, a beta-blocker that suppresses RyR2 activity and CPVT, promoted Ca2+ alternans in these hearts. Thus, RyR2 function is an important determinant of Ca2+ , APD, and ECG alternans. Our data also indicate that the activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner. Therefore, overly suppressing or enhancing RyR2 function is pro-arrhythmic.