HDAC2-dependent remodeling of KCa2.2 (KCNN2) and KCa2.3 (KCNN3) K+ channels in atrial fibrillation with concomitant heart failure
HDAC2-dependent remodeling of KCa2.2 (KCNN2) and KCa2.3 (KCNN3) K+ channels in atrial fibrillation with concomitant heart failure
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DOI：
10.1016/j.lfs.2020.118892
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发表时间：
2021-02-01
期刊：
影响因子：
6.1
通讯作者：
Lugenbiel, Patrick
中科院分区：
文献类型：
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作者：
Rahm, Ann-Kathrin;Wieder, Teresa;Lugenbiel, Patrick
目的：房颤（AF）伴心力衰竭（HF）与心房不应期延长相关。小电导，钙激活的K+（K-Ca，KCNN）通道促进动作电位（AP）复极。KCNN 2和KCNN 3变异与房颤风险相关。此外，组蛋白去乙酰化酶（HDAC）相关的表观遗传机制已牵连在AP的调节。我们假设HDAC 2依赖性KCNN 2和KCNN 3表达的重构有助于AF合并HF的心房颤动发生。目的是评估HDAC 2和KCNN 2/3的转录水平在AF/HF患者和猪模型，并探讨细胞表观遗传效应HDAC 2失活KCNN expression.Materials和方法：HDAC 2和KCNN 2/3的转录水平进行了定量的AF和HF患者，并在猪模型的心房快速起搏诱导的AF和左心室功能降低。在HL-1心房肌细胞中采用快速起搏和抗Hdac 2 siRNA治疗来研究对KCNN 2/3 mRNA和KCa蛋白丰度的影响。关键发现：AF/HF患者和相应的猪模型中心房KCNN 2和KCNN 3表达减少。HDAC 2在人类中显示出显著的下调，并且在猪的右心房组织中表现出降低表达的趋势。快速起搏概括了Kcnn 2/K（Ca）2.2、Kcnn 3/K（Ca）2.3和Hdac 2/HDAC 2的下调，表明高心房率触发表观遗传重构机制。最后，在体外敲低Hdac 2可降低Kcnn 3/KCa 2.3的表达。意义：Kcnn 2/3和HDAC 2的表达在AF合并HF中受到抑制。Hdac 2直接调节心房细胞中Kcnn 3 mRNA水平。AF中表观遗传电生理效应的机制和治疗意义需要进一步验证。
Aims: Atrial fibrillation (AF) with concomitant heart failure (HF) is associated with prolonged atrial refractoriness. Small-conductance, calcium-activated K+ (K-Ca, KCNN) channels promote action potential (AP) repolarization. KCNN2 and KCNN3 variants are associated with AF risk. In addition, histone deacetylase (HDAC)-related epigenetic mechanisms have been implicated in AP regulation. We hypothesized that HDAC2-dependent remodeling of KCNN2 and KCNN3 expression contributes to atrial arrhythmogenesis in AF complicated by HF. The objectives were to assess HDAC2 and KCNN2/3 transcript levels in AF/HF patients and in a pig model, and to investigate cellular epigenetic effects of HDAC2 inactivation on KCNN expression.Materials and methods: HDAC2 and KCNN2/3 transcript levels were quantified in patients with AF and HF, and in a porcine model of atrial tachypacing-induced AF and reduced left ventricular function. Tachypacing and anti-Hdac2 siRNA treatment were employed in HL-1 atrial myocytes to study effects on KCNN2/3 mRNA and KCa protein abundance.Key findings: Atrial KCNN2 and KCNN3 expression was reduced in AF/HF patients and in a corresponding pig model. HDAC2 displayed significant downregulation in humans and a tendency towards reduced expression in right atrial tissue of pigs. Tachypacing recapitulated downregulation of Kcnn2/K(Ca)2.2, Kcnn3/K(Ca)2.3 and Hdac2/HDAC2, indicating that high atrial rates trigger epigenetic remodeling mechanisms. Finally, knock-down of Hdac2 in vitro reduced Kcnn3/KCa2.3 expression.Significance: KCNN2/3 and HDAC2 expression is suppressed in AF complicated by HF. Hdac2 directly regulates Kcnn3 mRNA levels in atrial cells. The mechanistic and therapeutic significance of epigenetic electrophysiological effects in AF requires further validation.