Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart.
Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart.
复制标题
DOI：
10.1161/circresaha.120.317349
复制
发表时间：
2020-12-04
影响因子：
20.1
通讯作者：
Fishman GI
中科院分区：
文献类型：
--
作者：
Park DS;Shekhar A;Santucci J 3rd;Redel-Traub G;Solinas S;Mintz S;Lin X;Chang EW;Narke D;Xia Y;Goldfarb M;Fishman GI
成纤维细胞生长因子同源因子（FHF）是钠通道失活的关键调节因子。这些关键蛋白质的突变与人类疾病有关，包括布鲁格达综合征、特发性室性心律失常和癫痫性脑病。 Fhf2 敲除小鼠钠通道可用性降低导致组织水平异常兴奋的潜在离子机制尚不清楚。使用动物模型和理论上的多细胞线性链，我们研究了 FHF2 如何协调钠、钙和间隙连接电导的相互依赖性以保护心脏传导。通过使用维拉帕米降低钙电导或使用甘诺索酮降低间隙连接电导或通过回交至连接蛋白 43 杂合 (Cx43+/-) 背景来挑战 Fhf2KO 小鼠。所有条件都会在 Fhf2KO 小鼠中产生传导阻滞，而 Fhf2WT 显示出正常的脉冲传播。为了探索 Fhf2KO 心脏中的离子阻断机制，构建了结合 FHF2 缺陷的钠通道失活特性的多细胞线性链模型，并忠实地再现了突变心脏中观察到的传导异常。钙电导降低或间隙连接解偶联的突变链中传导阻滞的机制非常不同。 FHF2 缺乏导致钠通道失活增强，从而改变了对钙电流的依赖，以维持细胞间的电紧张驱动力、轴向电流和动作电位的产生。在间隙连接解偶联的情况下，上游细胞较慢的充电时间与突变链中钠通道失活的加速相结合，以防止下游细胞为动作电位传播提供足够的充电。 FHF2 依赖性对钠通道失活的影响确保了足够的钠电流储备，以防止对可靠的心脏冲动传播的众多威胁。
Fibroblast growth factor homologous factors (FHFs) are key regulators of sodium channel inactivation. Mutations in these critical proteins have been implicated in human diseases including Brugada syndrome, idiopathic ventricular arrhythmias, and epileptic encephalopathy. The underlying ionic mechanisms by which reduced sodium channel availability in Fhf2 knockout mice predisposes to abnormal excitability at the tissue level are not well defined. Using animal models and theoretical multicellular linear strands, we examined how FHF2 orchestrates the interdependency of sodium, calcium, and gap junctional conductances to safeguard cardiac conduction. Fhf2KO mice were challenged by reducing calcium conductance using verapamil or by reducing gap junctional conductance using carbenoxolone or by backcrossing into a connexin 43 heterozygous (Cx43+/−) background. All conditions produced conduction block in Fhf2KO mice, with Fhf2WT showing normal impulse propagation. To explore the ionic mechanisms of block in Fhf2KO hearts, multicellular linear strand models incorporating FHF2-deficient sodium channel inactivation properties were constructed and faithfully recapitulated conduction abnormalities seen in mutant hearts. The mechanisms of conduction block in mutant strands with reduced calcium conductance or gap junction uncoupling are very different. Enhanced sodium channel inactivation due to FHF2 deficiency shifts dependence onto calcium current to sustain electrotonic driving force, axial current flow, and action potential generation from cell-to-cell. In the setting of gap junction uncoupling, slower charging time from upstream cells conspires with accelerated sodium channel inactivation in mutant strands to prevent sufficient downstream cell charging for action potential propagation. FHF2-dependent effects on sodium channel inactivation ensure adequate sodium current reserve to safeguard against numerous threats to reliable cardiac impulse propagation.