Molecular basis of transient outward potassium current downregulation in human heart failure -: A decrease in Kv4.3 mRNA correlates with a reduction in current density
Molecular basis of transient outward potassium current downregulation in human heart failure -: A decrease in Kv4.3 mRNA correlates with a reduction in current density
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DOI：
10.1161/01.cir.98.14.1383
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发表时间：
1998-10-06
期刊：
影响因子：
37.8
通讯作者：
Tomaselli, GF
中科院分区：
文献类型：
--
作者：
Kääb, S;Dixon, J;Tomaselli, GF
背景-尽管医学治疗取得了进展，但充血性心力衰竭仍然是发达国家死亡的主要原因，不成比例的心力衰竭患者的死亡是突然的，并被认为是心力衰竭。在人类和动物模型中，心力衰竭与动作电位时程（APD）的延长有关，APD是K+电流下调的结果-显著地，Ca 2+非依赖性瞬时外向电流（I-to）。心力衰竭时I-to降低的机制尚不清楚。的K+通道α-亚基Kv 4，3，果蝇Shal家族的同源物，是最有可能编码的全部或部分的本地心脏I-to在human.Methods和Results-We使用核糖核酸酶保护试验和全细胞电生理记录研究的Kv4.3 mRNA和I-to在人体组织和分离的心室肌细胞，分别在水平的变化。我们发现，与非衰竭对照组相比，衰竭心脏中Kv 4，3 mRNA的水平下降了30%。此外，这种降低与从心脏邻近区域分离的心室肌细胞中测量的峰值I-to密度的降低相关。研究的任何其他mRNA（HERG、Kv 1，4、Kir2.1、Kv β 1，3和Ca 2+通道的α 1C亚基）的稳态水平均无显著变化。在人心室中发现了低丰度的编码Kv 1，2，Kv 1，5和Kv2.1的mRNA。结论-这些数据进一步支持了Kv4.3编码人类全部或部分天然心脏I-to的假设，以及心力衰竭中该电流的部分下调可能是转录调节的。
Background-Despite advances in medical therapy, congestive heart failure remains a major cause of death in the developed world, A disproportionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic, Heart failure in humans and in animal models is associated with prolongation of the action potential duration (APD), the result of downregulation of K+ currents-prominently, the Ca2+-independent transient outward current (I-to). The mechanism for the reduction of I-to in heart failure is unknown. The K+ channel alpha-subunit Kv4,3, a homolog of the Drosophila Shal family, is most likely to encode all or part of the native cardiac I-to in humans.Methods and Results-We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and I-to in human tissues and isolated ventricular myocytes, respectively. We found that the level of Kv4,3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Furthermore, this reduction correlated with the reduction in peak I-to density measured in ventricular myocytes isolated from adjacent regions of the heart. There was no significant change in the steady-state level of any other mRNA studied (HERG, Kv1,4, Kir2.1, Kv beta 1,3, and the alpha 1C subunit of the Ca2+ channel). mRNAs encoding Kv1,2, Kv1,5, and Kv2.1 were found in low abundance in human ventricle,Conclusions-These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac I-to in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.