Modulation of the cardiac sodium channel NaV1.5 peak and late currents by NAD+ precursors.
Modulation of the cardiac sodium channel NaV1.5 peak and late currents by NAD+ precursors.
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NAD 前体对心脏钠通道 NaV1.5 峰值电流和晚电流的调节。
DOI：
10.1016/j.yjmcc.2020.01.013
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发表时间：
2020
影响因子：
5
通讯作者：
London,Barry
中科院分区：
文献类型：
--
作者：
Matasic,DanielS;Yoon,Jin-Young;McLendon,JaredM;Mehdi,Haider;Schmidt,MarkS;Greiner,AlexanderM;Quinones,Pravda;Morgan,GinaM;Boudreau,RyanL;Irani,Kaikobad;Brenner,Charles;London,Barry
心脏钠通道NaV1.5由SCN 5A编码，产生快速失活去极化电流INA，负责心脏动作电位的启动和传播。获得性和遗传性NaV1.5功能障碍导致峰值INa降低或残余晚期INa（INa，L）增加，导致快速/缓慢心律失常和心源性猝死。已有研究表明，细胞内NAD+和NAD+/NADH比值增加，通过抑制线粒体活性氧和PKC介导的NaV1.5磷酸化，增加INa。此外，Sirtuin 1在K1479处对NaV1.5的NAD+依赖性脱乙酰化增加NaV1.5膜运输和INa。目的探讨NAD+前体烟酰胺核苷（nicotinamide riboside，NR）和烟酰胺（nicotinamide，NAM）是否以及通过何种机制影响峰值INa和INa，体外和体内心脏电生理。方法和结果采用表达野生型和突变型NaV1.5的HEK 293细胞、大鼠新生心肌细胞（RNCMs）、和老鼠。NR增加表达NaV1.5的HEK 293细胞中的I（500 μM：51 ± 18%，p = .02，5 mM：59 ± 22%，p = .03）和RNCM（500 μM：60 ± 26%，p = 0.02，5 mM：74 ± 39%，p = 0.03），同时在较高浓度下降低INa，Lat（RNCM，5 mM：−45 ± 11%，p = 0.04）。NR（5 mM）降低NaV1.5 K1479乙酰化，但增加表达NaV1.5突变形式的HEK 293细胞中的INa，并破坏乙酰化位点（NaV1.5-K1479 A）。PKC磷酸化位点的破坏取消了NR对INa的影响。此外，NAM（5 mM）对INain RNCM或表达野生型NaV1.5的HEK 293细胞没有影响，但增加了表达NaV1.5-K1479 A的HEK 293细胞的INain。在C57 BL/6 J小鼠中，连续10-12周补充NR可降低QTc（0.35%NR：−4.9 ± 2.0%，p = 0.14; 1.0%NR：−9.5 ± 2.8%，p = 0.01）。NR增加INa，降低INa，L，并值得进一步研究作为NaV1.5缺乏和/或功能障碍引起的糖尿病疾病的潜在治疗方法。
RationaleThe cardiac sodium channel NaV1.5, encoded bySCN5A, produces the rapidly inactivating depolarizing current INathat is responsible for the initiation and propagation of the cardiac action potential. Acquired and inherited dysfunction of NaV1.5 results in either decreased peak INaor increased residual late INa(INa,L), leading to tachy/bradyarrhythmias and sudden cardiac death. Previous studies have shown that increased cellular NAD+and NAD+/NADH ratio increase INathrough suppression of mitochondrial reactive oxygen species and PKC-mediated NaV1.5 phosphorylation. In addition, NAD+-dependent deacetylation of NaV1.5 at K1479 by Sirtuin 1 increases NaV1.5 membrane trafficking and INa. The role of NAD+precursors in modulating INaremains unknown.ObjectiveTo determine whether and by which mechanisms the NAD+precursors nicotinamide riboside (NR) and nicotinamide (NAM) affect peak INaand INa,Lin vitroand cardiac electrophysiologyin vivo.Methods and resultsThe effects of NAD+precursors on the NAD+metabolome and electrophysiology were studied using HEK293 cells expressing wild-type and mutant NaV1.5, rat neonatal cardiomyocytes (RNCMs), and mice. NR increased INain HEK293 cells expressing NaV1.5 (500 μM: 51 ± 18%,p= .02, 5 mM: 59 ± 22%,p= .03) and RNCMs (500 μM: 60 ± 26%, p = .02, 5 mM: 74 ± 39%, p = .03) while reducing INa,Lat the higher concentration (RNCMs, 5 mM: −45 ± 11%,p= .04). NR (5 mM) decreased NaV1.5 K1479 acetylation but increased INain HEK293 cells expressing a mutant form of NaV1.5 with disruption of the acetylation site (NaV1.5-K1479A). Disruption of the PKC phosphorylation site abolished the effect of NR on INa. Furthermore, NAM (5 mM) had no effect on INain RNCMs or in HEK293 cells expressing wild-type NaV1.5, but increased INain HEK293 cells expressing NaV1.5-K1479A. Dietary supplementation with NR for 10–12 weeks decreased QTc in C57BL/6 J mice (0.35% NR: −4.9 ± 2.0%,p= .14; 1.0% NR: −9.5 ± 2.8%,p= .01).ConclusionsNAD+precursors differentially regulate NaV1.5viamultiple mechanisms. NR increases INa, decreases INa,L, and warrants further investigation as a potential therapy for arrhythmic disorders caused by NaV1.5 deficiency and/or dysfunction.
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