SIRT1抑制剂EX-527通过抑制INaL减少小鼠室性心律失常*

doi:10.3870/j.issn.1672-0741.25.11.020

华中科技大学学报（医学版） ›› 2026, Vol. 55 ›› Issue (5): 624-631.doi: 10.3870/j.issn.1672-0741.25.11.020

SIRT1抑制剂EX-527通过抑制I_NaL减少小鼠室性心律失常^*

张敏^#, 马国兰^#, 刘治杰, 罗岸涛^△

武汉科技大学医学院,职业危害识别与控制湖北省重点实验室,心血管研究所,武汉 430065

收稿日期:2025-11-13 发布日期:2026-10-30
通讯作者: ^△E-mail：lat78@126.com
作者简介:张敏,女,2001年生,硕士研究生,E-mail：1939790110@qq.com;马国兰,女,1998年,硕士研究生,E-mail：547682020@qq.com; ^#共同第一作者
基金资助:
^*湖北省教育厅科学研究计划项目（No. B2024015）

SIRT1 Inhibitor EX-527 Suppresses Ventricular Arrhythmias by Selectively Reducing Late Sodium Current in Mouse Ventricular Myocytes

Zhang Min^#, Ma Guolan^#, Liu Zhijie et al

Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification, Control, School of Medicine, Wuhan University of Science, Technology, Wuhan 430065, China

Received:2025-11-13 Published:2026-10-30
Contact: ^△E-mail：lat78@126.com

摘要/Abstract

摘要： 目的探究去乙酰化酶SIRT1的特异性抑制剂EX-527对心肌细胞离子电流及心律失常的作用及机制。方法采用全细胞膜片钳技术研究EX-527对正常条件下小鼠心室肌细胞晚钠电流（I_NaL）等离子电流,以及对海葵毒素（ATXⅡ,I_NaL开放剂）或主动脉弓缩窄术（TAC）所致心衰时病理增大的I_NaL的作用;应用在体心电图记录研究EX-527对ATXⅡ诱发的小鼠室性心律失常的作用,并探讨其机制。采用Western blot检测p-CaMKⅡ和p-PKC的表达水平。结果 ①EX-527（10 μmol/L）可显著抑制ATXⅡ（2 nmol/L）诱导增大的I_NaL;②EX-527（10 μmol/L）对I_Na,I_CaL,I_K1,I_K及I_to等电流无明显作用;③CaMKⅡ抑制剂KN-93（10 μmol/L）与PKC抑制剂BIM（2 μmol/L）联合应用完全阻断了EX-527对I_NaL的作用;④心衰小鼠心室肌细胞的I_NaL较假手术组增大,且能被EX-527明显抑制;⑤EX-527（10 μmol/L）缩短了ATXⅡ延长的动作电位时程并完全消除其诱导的早后除极;⑥EX-527明显减少ATXⅡ所致室颤和室速的发生率及持续时间;⑦EX-527降低p-CaMKⅡ和p-PKC的表达水平。结论急性应用EX-527可通过CaMKⅡ和PKC通路抑制心室肌细胞I_NaL,继而减少小鼠室性心律失常的发生。

关键词: EX-527, 晚钠电流, 心律失常, SIRT1, 膜片钳技术

Abstract: Objective To investigate the effects and mechanisms of EX-527, a specific SIRT1 inhibitor, on cardiac ion currents and arrhythmias in ventricular myocytes. Methods The whole-cell patch clamp technique was used to examine the effects of EX-527 on I_NaL and other ionic currents in mouse ventricular myocytes under normal conditions, as well as on the enhanced I_NaL induced by anemone toxinⅡ （ATXⅡ, an I_NaL enhancer） or by heart failure resulting from transverse aortic constriction （TAC）. In vivo electrocardiography was performed to evaluate the effects of EX-527 on ATXⅡ-induced ventricular arrhythmias in mice. The expression levels of p-CaMKⅡ and p-PKC were detected by Western blotting. Results ① EX-527 （10 µmol/L） inhibited the ATXⅡ-enhanced I_NaL in ventricular myocytes; ②EX-527 （10 µmol/L） had no significant effects on I_Na, I_CaL, I_K, I_K1 or I_to; ③Combined inhibition of CaMKⅡ（10 µmol/L KN-93） and PKC （2 µmol/L BIM） nearly completely eliminated the inhibitory effect of EX-527 on ATXⅡ-enhanced I_NaL; ④EX-527 inhibited the enhanced I_NaL induced by TAC; ⑤EX-527 shortened the prolonged action potential duration and completely eliminated early afterdepolarizations induced by ATXⅡ ⑥EX-527 significantly reduced the incidence and duration of ventricular tachycardia and ventricular fibrillation induced by ATXⅡ ⑦EX-527 reduced the expression levels of p-CaMKⅡ and p-PKC. Conclusion Acute application of EX-527 protects against ventricular arrhythmias by selectively inhibiting I_NaL in ventricular myocytes via both CaMKⅡ and PKC signaling pathways.

Key words: EX-527, late sodium current, cardiac arrhythmia, SIRT1, patch clamp technique

中图分类号:

R541.7

张敏, 马国兰, 刘治杰, 罗岸涛. SIRT1抑制剂EX-527通过抑制I_NaL减少小鼠室性心律失常^*[J]. 华中科技大学学报（医学版）, 2026, 55(5): 624-631.

Zhang Min, Ma Guolan, Liu Zhijie et al. SIRT1 Inhibitor EX-527 Suppresses Ventricular Arrhythmias by Selectively Reducing Late Sodium Current in Mouse Ventricular Myocytes[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(5): 624-631.

参考文献

[1] Plant L D,Xiong D,Romero J,et al.Hypoxia produces pro-ar-rhythmic late sodium current in cardiac myocytes by SUMOylation of Na(V)_1.5 channels[J].Cell Rep,2020,30(7):2225-2236.
[2] Zeng B,Liao X,Liu L,et al.Thyroid hormone diminishes Ca²⁺ overload induced by hypoxia/reoxygenation in cardiomyocytes by inhibiting late sodium current and reverse-Na⁺/Ca²⁺ exchange current[J].Pharmacology,2020,105(1/2):63-72.
[3] Yu S,Li G,Huang C L H,et al.Late sodium current associated cardiac electrophysiological and mechanical dysfunction[J].Pflügers Arch Eur J Physiol,2018,470(3):461-469.
[4] Lin Q,Zuo W,Liu Y,et al.NAD⁺ and cardiovascular diseases[J].Clin Chim Acta,2021,515:104-110.
[5] Shryock J C,Song Y,Rajamani S,et al.The arrhythmogenic consequences of increasing late I_Na in the cardiomyocyte[J].Cardiovasc Res,2013,99(4):600-611.
[6] Antzelevitch C,Nesterenko V,Shryock J C,et al.The role of late I_Na in development of cardiac arrhythmias[M]//Ruben P C.Voltage Gated Sodium Channels.Berlin,Heidelberg:Sp-ringer,2014::137-168.
[7] Serio S,Pagiatakis C,Musolino E,et al.Cardiac aging is promoted by pseudohypoxia increasing p300-induced glycolysis[J].Circ Res,2023,133(8):687-703.
[8] Chen C,Zhou M,Ge Y,et al.SIRT1 and aging related signaling pathways[J].Mech Ageing Dev,2020,187:111215.
[9] Matasic D S,Yoon J Y,McLendon J M,et al.Modulation of the cardiac sodium channel Na(V)_1.5 peak and late currents by NAD(+) precursors[J].J Mol Cell Cardiol,2020,141:70-81.
[10] Qian C, Ma J, Zhang P, et al.Resveratrol attenuates the Na⁺-dependent intracellular Ca²⁺overload by inhibiting H₂O₂-in-duced increase in late sodium current in ventricular myocytes[J]. PLoS One,2012,7(12):e51358.
[11] Wu D,Hu Q,Liu X,et al.Hydrogen sulfide protects against apoptosis under oxidative stress through SIRT1 pathway in H9c2 cardiomyocytes[J].Nitric Oxide,2015,46:204-212.
[12] Li S H,Ma G L,Zhang S L,et al.Naringin exerts antiarrhythmic effects by inhibiting channel currents in mouse cardiomyocytes[J].J Electrocardiol,2023,80:69-80.
[13] Miranda V M,Beserra S S,Campos D R.Inotropic and antiarrhythmic transmural actions of ranolazine in a cellular model of type 3 long QT syndrome[J].Arq Bras Cardiol,2020,114(4):732-735.
[14] Vikram A,Lewarchik C M,Yoon J Y,et al.Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel[J].Nat Med,2017,23(3):361-367.
[15] Yang H Y,Lin F Z,Yang H W,et al.The effect of Sirt1 deficiency on Ca²⁺ and Na⁺ regulation in mouse ventricular myocytes[J].J Cell Mol Med,2020,24(12):6762-6772.
[16] Wallace C H,Baczkó I,Jones L,et al.Inhibition of cardiac voltage-gated sodium channels by grape polyphenols[J].Br J Pharmacol,2006,149(6):657-665.
[17] Li W,Wang Y P,Gao L,et al.Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca²⁺ overload[J].Acta Pharmacol Sin,2013,34(9):1164-1173.
[18] Iqbal S M,Lemmens-Gruber R.Phosphorylation of cardiac voltage-gated sodium channel:potential players with multiple dimensions[J].Acta Physiol,2019,225(3):e13210.
[19] Burashnikov A,Antzelevitch C.Late-phase 3 EAD.A unique mechanism contributing to initiation of atrial fibrillation[J].Pacing Clin Electrophysiol,2006,29(3):290-295.
[20] Ma J,Luo A,Wu L,et al.Calmodulin kinaseⅡand protein kinase C mediate the effect of increased intracellular calcium to augment late sodium current in rabbit ventricular myocytes[J].Am J Physiol Cell Physiol,2012,302(8):C1141-C1151.
[21] Mohler P J,Hund T J.Role of CaMKII in cardiovascular health,disease,and arrhythmia[J].Heart Rhythm,2011,8(1):142-144.
[22] Liang F,Fan P,Jia J,et al.Inhibitions of late I Na and CaMKII act synergistically to prevent ATX-Ⅱ-induced atrial fibrillation in isolated rat right atria[J].J Mol Cell Cardiol,2016,94:122-130.
[23] Kornyeyev D,El-Bizri N,Hirakawa R,et al.Contribution of the late sodium current to intracellular sodium and calcium overload in rabbit ventricular myocytes treated by anemone toxin[J].Am J Physiol Heart Circ Physiol,2016,310(3):H426-H435.
[24] Coppini R,Santini L,Olivotto I,et al.Abnormalities in sodium current and calcium homoeostasis as drivers of arrhythmogenesis in hypertrophic cardiomyopathy[J].Cardiovasc Res,2020,116(9):1585-1599.
[25] Fiorentino F,Fabbrizi E,Mai A,et al.Activation and inhibition of sirtuins:From bench to bedside[J].Med Res Rev,2025,45(2):484-560.
[26] Liu J,Ai Y,Niu X,et al.Taurine protects against cardiac dysfunction induced by pressure overload through SIRT1-p53 activation[J].Chem Biol Interact,2020,317:108972.

SIRT1抑制剂EX-527通过抑制I_NaL减少小鼠室性心律失常^*

SIRT1 Inhibitor EX-527 Suppresses Ventricular Arrhythmias by Selectively Reducing Late Sodium Current in Mouse Ventricular Myocytes

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