Magnesium Deficiency Causes Transcriptional Downregulation of Kir2.1 and Kv4.2 Channels in Cardiomyocytes Resulting in QT Interval Prolongation
Magnesium Deficiency Causes Transcriptional Downregulation of Kir2.1 and Kv4.2 Channels in Cardiomyocytes Resulting in QT Interval Prolongation
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DOI：
10.1253/circj.cj-20-0310
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发表时间：
2020-08-01
影响因子：
3.3
通讯作者：
Ono, Katsushige
中科院分区：
文献类型：
--
作者：
Shimaoka, Toru;Wang, Yan;Ono, Katsushige
背景：低镁血症时 QT 间期延长和心律失常发生的机制尚不清楚。本研究利用膜片钳技术和分子生物学研究了镁（Mg）缺乏引起的大鼠QT延长的潜在分子机制。方法和结果：雄性Wistar大鼠饲喂无镁饮食或正常饮食长达12周。缺镁大鼠的心电图显示 QT 间期延长，这些大鼠的心肌细胞显示动作电位持续时间延长。电生理学研究表明，缺镁心肌细胞内向整流 K+ 电流 (I-K1) 和瞬时外向 K+ 电流 (I-to) 降低，这些结果与 mRNA 以及 Kir2.1 和 Kv4.2 蛋白水平的下调一致。在缺镁的心肌细胞中，转录因子 GATA4 和 NFAT 上调，而 CREB 下调。与镁缺乏相反，培养的心肌细胞中的细胞Mg2+超载导致Kir2.1和Kv4.2上调，伴随着GATA4和NFATc4下调以及CREB上调。 NFAT 的激活和 CREB 的抑制会降低 Kv4.2-I-to，而 CREB 的抑制会降低 Kir2.1-I-K1，但 NFTA 的激活不会降低 Kir2.1-I-K1。结论：细胞内镁缺乏会下调心肌细胞中的 I-K1 和 I-to，这是由转录因子 NFAT 和 CREB 介导的。这些结果为低镁血症中长期QT间期延长提供了新的机制。
Background: Mechanisms for QT interval prolongation and cardiac arrhythmogenesis in hypomagnesemia are poorly understood. This study investigated the potential molecular mechanism for QT prolongation caused by magnesium (Mg) deficiency in rats by using the patch clamp technique and molecular biology.Methods and Results: Male Wistar rats were fed an Mg-free diet or a normal diet for up to 12 weeks. There was QT prolongation in the ECG of Mg-deficient rats, and cardiomyocytes from these rats showed prolongation of action potential duration. Electrophysiological studies showed that inward-rectifying K+ current (I-K1) and transient outward K+ current (I-to) were decreased in Mg-deficient cardiomyocytes, and these findings were consistent with the downregulation of mRNA, as well as protein levels of Kir2.1 and Kv4.2. In Mg-deficient cardiomyocytes, transcription factors, GATA4 and NFAT, were upregulated, whereas CREB was downregulated. In contrast to Mg deficiency, cellular Mg2+ overload in cultured cardiomyocytes resulted in the upregulation of Kir2.1 and Kv4.2, which was accompanied by the downregulation of GATA4 and NFATc4, and the upregulation of CREB. Activation of NFAT and inhibition of CREB reduced Kv4.2-I-to, whereas Kir2.1-I-K1 was reduced by CREB inhibition but not by NFTA activation.Conclusions: Intracellular Mg deficiency downregulates I-K1 and I-to in cardiomyocytes, and this is mediated by the transcription factors, NFAT and CREB. These results provide a novel mechanism for the long-term QT interval prolongation in hypomagnesemia.