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

doi:10.3870/j.issn.1672-0741.25.11.020

Abstract

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

CLC Number:

R541.7

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.

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