Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death.
Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death.
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DOI：
10.1161/circgenetics.113.000315
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发表时间：
2014-02
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影响因子：
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通讯作者：
Abbott GW
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文献类型：
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作者：
Hu Z;Kant R;Anand M;King EC;Krogh-Madsen T;Christini DJ;Abbott GW
心源性猝死（SCD）是全球主要的死亡原因，在糖尿病患者中的发病率增加。离子通道基因扰动为SCD提供了一个明确的心室致心律失常底物。然而，大多数心律失常易感基因-包括KCNE 2 K+通道β亚基-在多种组织中表达，表明潜在的多重SCD底物。使用“全转录物”转录组学，我们发现了P21 Kcne 2 −/−小鼠幼仔心脏血管紧张素原上调和心脏血管紧张素原相互作用网络的重塑，以及与成年Kcne 2 −/−小鼠代谢综合征一致的肾上腺重塑。这导致发现Kcne 2破坏引起多种公认的心外来源的SCD底物：糖尿病、高胆固醇血症、高钾血症、贫血和升高的血管紧张素II。Kcne 2缺失也是年龄依赖性QT间期延长、短暂性缺血后立即发生室颤和SCD以及空腹依赖性低血糖、心肌缺血和房室传导阻滞的先决条件。一个单一的，广泛表达的心律失常易感基因的破坏可以产生多系统综合征，包括多种电和全身底物和SCD的触发器。这一范例有望应用于其他心律失常易感基因，其中大多数编码普遍表达的离子通道亚基或调节蛋白。
Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in diabetics. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia susceptibility genes - including the KCNE2 K+ channel β subunit - are expressed in multiple tissues, suggesting potential multiplex SCD substrates. Using “whole transcript” transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2−/− mouse pups, and adrenal remodeling consistent with metabolic syndrome in adult Kcne2−/− mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes, hypercholesterolemia, hyperkalemia, anemia and elevated angiotensin II. Kcne2 deletion was also prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately following transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia and atrioventricular block. Disruption of a single, widely expressed arrhythmia susceptibility gene can generate a multisystem syndrome comprising manifold electrical and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.