Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel.
Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel.
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DOI：
10.1038/nm.4284
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发表时间：
2017-03
期刊：
影响因子：
82.9
通讯作者：
Irani K
中科院分区：
文献类型：
--
作者：
Vikram A;Lewarchik CM;Yoon JY;Naqvi A;Kumar S;Morgan GM;Jacobs JS;Li Q;Kim YR;Kassan M;Liu J;Gabani M;Kumar A;Mehdi H;Zhu X;Guan X;Kutschke W;Zhang X;Boudreau RL;Dai S;Matasic DS;Jung SB;Margulies KB;Kumar V;Bachschmid MM;London B;Irani K
由SCN 5A基因编码的电压门控心脏Na+通道（Nav1.5）传导内向去极化心脏Na+电流（INa），并且对于正常心脏电活动至关重要。SCN 5A中的遗传性功能丧失突变导致心脏电脉冲的产生和传导缺陷，并与各种心律失常表型相关。在这里，我们表明，sirtuin 1脱乙酰酶（Sirt 1）脱乙酰化Nav1.5在赖氨酸1479（K1479）和刺激INa通过赖氨酸脱乙酰化介导的Nav1.5到质膜的运输。小鼠心脏Sirt 1缺陷诱导Nav1.5中K1479的过度乙酰化，降低心肌细胞膜上Nav1.5的表达，降低INa，并导致心脏传导异常和心律失常导致的过早死亡。cardiac-Sirt 1缺陷小鼠的心律失常表型重现了Nav1.5功能丧失导致的人类心律失常。Sirt 1活性或表达增加导致Nav1.5的赖氨酸乙酰化降低，这促进Nav1.5向质膜的运输和INa的刺激。与野生型Nav1.5相比，K1479突变为不可乙酰化残基的Nav1.5增加了INa峰值，并且不受Sirt 1的调节，而K1479突变为模拟乙酰化的Nav1.5降低了INa。在心肌病和临床传导疾病患者的心脏中，Nav1.5在K1479上过度乙酰化。因此，Sirt 1通过去乙酰化Nav1.5，在调节INa和心脏电活动中起重要作用。
The voltage-gated cardiac Na+ channel (Nav1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na+ current (INa) and is vital for normal cardiac electrical activity. Inherited loss-of-function mutations in SCN5A lead to defects in the generation and conduction of the cardiac electrical impulse and are associated with various arrhythmia phenotypes. Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Nav1.5 at lysine 1479 (K1479) and stimulates INa via lysine-deacetylation-mediated trafficking of Nav1.5 to the plasma membrane. Cardiac Sirt1 deficiency in mice induces hyperacetylation of K1479 in Nav1.5, decreases expression of Nav1.5 on the cardiomyocyte membrane, reduces INa and leads to cardiac conduction abnormalities and premature death owing to arrhythmia. The arrhythmic phenotype of cardiac-Sirt1-deficient mice recapitulated human cardiac arrhythmias resulting from loss of function of Nav1.5. Increased Sirt1 activity or expression results in decreased lysine acetylation of Nav1.5, which promotes the trafficking of Nav1.5 to the plasma membrane and stimulation of INa. As compared to wild-type Nav1.5, Nav1.5 with K1479 mutated to a nonacetylatable residue increases peak INa and is not regulated by Sirt1, whereas Nav1.5 with K1479 mutated to mimic acetylation decreases INa. Nav1.5 is hyperacetylated on K1479 in the hearts of patients with cardiomyopathy and clinical conduction disease. Thus, Sirt1, by deacetylating Nav1.5, plays an essential part in the regulation of INa and cardiac electrical activity.
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影响因子：
24
作者：
McNair, William P.;Sinagra, Gianfranco;Taylor, Matthew R. G.;Di Lenarda, Andrea;Ferguson, Debra A.;Salcedo, Ernesto E.;Slavov, Dobromir;Zhu, Xiao;Caldwell, John H.;Mestroni, Luisa
通讯作者：
Mestroni, Luisa
影响因子：
15.9
作者：
Grant, AO;Carboni, MP;Priori, S
通讯作者：
Priori, S
DOI：
10.1152/ajpheart.00817.2010
发表时间：
2012-02-01
影响因子：
4.8
作者：
Hallaq, Haifa;Wang, Dao W.;Murray, Katherine T.
通讯作者：
Murray, Katherine T.
影响因子：
2.8
作者：
Yokokawa, Miki;Noda, Takashi;Shimizu, Wataru
通讯作者：
Shimizu, Wataru
心脏Na+电流对吡啶核苷酸的调节。
影响因子：
20.1
作者：
Liu, Man;Sanyal, Shamarendra;Gao, Ge;Gurung, Iman S.;Zhu, Xiaodong;Gaconnet, Georgia;Kerchner, Laurie J.;Shang, Lijuan L.;Huang, Christopher L-H.;Grace, Andrew;London, Barry;Dudley, Samuel C., Jr.
通讯作者：
Dudley, Samuel C., Jr.