Ca2+-Related Signaling and Protein Phosphorylation Abnormalities Play Central Roles in a New Experimental Model of Electrical Storm
Ca2+-Related Signaling and Protein Phosphorylation Abnormalities Play Central Roles in a New Experimental Model of Electrical Storm
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DOI：
10.1161/circulationaha.110.016683
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发表时间：
2011-05-24
期刊：
影响因子：
37.8
通讯作者：
Kamiya, Kaichiro
中科院分区：
文献类型：
--
作者：
Tsuji, Yukiomi;Hojo, Mayumi;Kamiya, Kaichiro
背景-电风暴（ES），以反复发作的室性心动过速/颤动为特征，通常发生在植入式心脏复律除颤器患者中，并对预后产生不利影响。然而，人们对潜在的分子基础知之甚少。在本研究中，我们报告了一种新的实验模型，其特点是植入式心律转复除颤器重复发作以治疗复发性心室颤动 (VF)，其中我们评估了 ES 中 Ca2+ 相关蛋白改变的参与情况。方法和结果 - 我们对 37 只完全房室传导阻滞的兔子进行了大约 80 天的研究，所有兔子均植入了植入式心律转复除颤器。所有兔子均表现出长 QT 和 VF 发作。 53% 的兔子出现 ES（每 24 小时内 >= 3 次 VF 发作；每只兔子 103 +/- 23 次 VF 发作）。使用以下指标评估兔子左心室组织中 Ca2+ 处理蛋白的表达/磷酸化：ES；出现 VF 发作，但不出现 ES（非 ES）；和控制。 ES 和非 ES 兔子的左心室舒张末期内径相对增加，但 ES 兔子的收缩功能障碍明显大于非 ES 兔子。与对照兔和非 ES 兔相比，ES 兔表现出明显的 Ca2+/钙调蛋白依赖性蛋白激酶 II 过度磷酸化、显着的受磷蛋白去磷酸化以及蛋白磷酸酶 1 和 2A 表达增加。在 ES 和非 ES 兔子中，兰尼碱受体 Ser2815 处的过度磷酸化类似，但与非 ES 兔子相比，兰尼碱受体 Ser2809 和 L 型 Ca2+ 通道 α 亚基过度磷酸化明显更高。为了检查重复 VF/除颤的直接影响，在对照兔子中诱导 VF 10 次。重复的室颤组织显示自磷酸化 Ca2+/钙调蛋白依赖性蛋白激酶 II 上调和受磷蛋白去磷酸化，与 ES 兔心脏相似。向ES兔持续输注钙调蛋白拮抗剂（W-7）可减少Ca2+/钙调蛋白依赖性蛋白激酶II过度磷酸化，抑制室性心动过速/颤动，并挽救左心室功能障碍。结论-ES引起Ca2+/钙调蛋白依赖性蛋白激酶II激活和受磷蛋白去磷酸化，这可以解释ES所特有的心律失常促进和机械功能障碍的恶性循环。 （流通。2011 年；123：2192-2203。）
Background-Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, typically occurs in implantable cardioverter-defibrillator patients and adversely affects prognosis. However, the underlying molecular basis is poorly understood. In the present study, we report a new experimental model featuring repetitive episodes of implantable cardioverter-defibrillator firing for recurrent ventricular fibrillation (VF), in which we assessed involvement of Ca2+-related protein alterations in ES.Methods and Results-We studied 37 rabbits with complete atrioventricular block for approximate to 80 days, all with implantable cardioverter-defibrillator implantation. All rabbits showed long-QT and VF episodes. Fifty-three percent of rabbits developed ES (>= 3 VF episodes per 24-hour period; 103 +/- 23 VF episodes per rabbit). Expression/phosphorylation of Ca2+-handling proteins was assessed in left ventricular tissues from rabbits with the following: ES; VF episodes but not ES (non-ES); and controls. Left ventricular end-diastolic diameter increased comparably in ES and non-ES rabbits, but contractile dysfunction was significantly greater in ES than in non-ES rabbits. ES rabbits showed striking hyperphosphorylation of Ca2+/calmodulin-dependent protein kinase II, prominent phospholamban dephosphorylation, and increased protein phosphatase 1 and 2A expression versus control and non-ES rabbits. Ryanodine receptors were similarly hyperphosphorylated at Ser2815 in ES and non-ES rabbits, but ryanodine receptor Ser2809 and L-type Ca2+-channel alpha-subunit hyperphosphorylation were significantly greater in ES versus non-ES rabbits. To examine direct effects of repeated VF/defibrillation, VF was induced 10 times in control rabbits. Repeated VF tissues showed autophosphorylated Ca2+/calmodulin-dependent protein kinase II upregulation and phospholamban dephosphorylation like those of ES rabbit hearts. Continuous infusion of a calmodulin antagonist (W-7) to ES rabbits reduced Ca2+/calmodulin-dependent protein kinase II hyperphosphorylation, suppressed ventricular tachycardia/fibrillation, and rescued left ventricular dysfunction.Conclusions-ES causes Ca2+/calmodulin-dependent protein kinase II activation and phospholamban dephosphorylation, which can explain the vicious cycle of arrhythmia promotion and mechanical dysfunction that characterizes ES. (Circulation. 2011; 123: 2192-2203.)