Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents.
Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents.
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DOI：
10.1161/circresaha.116.309877
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发表时间：
2016-12-09
影响因子：
20.1
通讯作者：
Rentschler S
中科院分区：
文献类型：
--
作者：
Khandekar A;Springer S;Wang W;Hicks S;Weinheimer C;Diaz-Trelles R;Nerbonne JM;Rentschler S
室性心律失常常发生在浦肯野-肌细胞交界处，是心源性猝死的主要原因。Notch激活将心肌细胞重编程为“诱导的浦肯野样”状态，其特征是动作电位持续时间延长和浦肯野富集基因的表达。了解典型Notch信号导致动作电位延长的机制。我们发现，与心室肌细胞相比，内源性浦肯野细胞降低了峰值K+电流，Ito和IK，速度较慢。Notch激活降低了外向K+电流的峰值密度，并减缓了外向K+电流分量Ito、f和IK，这与部分重编程向类似浦肯病表型的方向一致。对notch激活脑室的基因表达研究表明，purkinji富集基因Contactin-2和Scn5a上调，而导致Ito、f和IK缓慢的K+通道亚基基因下调。相反，Notch信号的失活导致细胞大小增加，与K+电流振幅的增加相称，并模拟生理性肥大。缺口诱导的K+电流密度的变化至少部分是通过转录变化来调节的。染色质免疫沉淀显示动态RBP-J结合和K+通道亚基启动子上活性组蛋白标记的丢失，具有Notch激活，在心力衰竭模型中也发生了类似的转录和表观遗传变化。有趣的是，Notch靶基因表达和细胞电生理反应在左心室和右心室心肌细胞中存在差异。总之，这些发现证明了在心脏病理环境下电压门控钾电流调节的新机制，并可能为心律失常药物设计提供新的靶点。
Ventricular arrhythmias often arise from the Purkinje-myocyte junction and are a leading cause of sudden cardiac death. Notch activation reprograms cardiac myocytes to an “induced Purkinje-like” state characterized by prolonged action potential duration and expression of Purkinje enriched genes. To understand the mechanism by which canonical Notch signaling causes action potential prolongation. We find that endogenous Purkinje cells have reduced peak K+ current, Ito and IK,slow when compared with ventricular myocytes. Consistent with partial reprogramming toward a Purkinje-like phenotype, Notch activation decreases peak outward K+ current density, as well as the outward K+ current components Ito,f and IK,slow. Gene expression studies in Notch-activated ventricles demonstrate upregulation of Purkinje-enriched genes Contactin-2 and Scn5a, as well as downregulation of K+ channel subunit genes that contribute to Ito,f and IK,slow. In contrast, inactivation of Notch signaling results in increased cell size commensurate with increased K+ current amplitudes and mimics physiologic hypertrophy. Notch-induced changes in K+ current density are regulated at least in part via transcriptional changes. Chromatin immunoprecipitation demonstrates dynamic RBP-J binding and loss of active histone marks on K+ channel subunit promoters with Notch activation, and similar transcriptional and epigenetic changes occur in a heart failure model. Interestingly, there is a differential response in Notch target gene expression and cellular electrophysiology in left versus right ventricular cardiac myocytes. In summary, these findings demonstrate a novel mechanism for regulation of voltage-gated potassium currents in the setting of cardiac pathology, and may provide a novel target for arrhythmia drug design.