SIRT1 inhibitor EX-527 inhibits ventricular arrhythmias by selectively reducing late Na⁺ current in mice ventricular myocytes

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

^* Corresponding author’s email: lat78@126.com

Abstract

A significant aspect in causing arrhythmia in some pathological situations (e.g., myocardial ischemia, heart failure, etc.) is an increase in late sodium current (I_NaL) in ventricular myocytes; reduction of I_NaL is a novel target for heart failure therapy. Deacetylase SIRT1 has a variety of cardioprotective effects, but whether it exerts antiarrhythmic effects by inhibiting I_NaL remains to be studied. In previous experiments, it was found that SRT2104, a specific agonist of SIRT1, could inhibit I_NaL and ventricular arrhythmias induced by anemone toxin (ATX II). Furthermore, EX-527, a specific inhibitor of SIRT1, was used for the verification experiment, and it was found that EX-527 could also inhibit I_NaL, but there was no study of I_NaL by EX-527. In this study, whole-cell patch clamp technique and in vivo electrocardiogram recording were used to investigate the effect and mechanism of EX-527 (10 μM) on I_NaL in pathologically enlarged mouse ventricular myocytes such as ATX II (2 nM) or heart failure. The following are the study’s main findings: (1) EX-527 inhibited the ATX II-enhanced I_NaL (Fig. 1 A, B); (2) The inhibition of ATX II-enhanced I_NaL by EX-527 is stronger than that by SRT2104 (Fig. 1 C, E); (3) A combined inhibition of CaMKII and PKC nearly completely eliminated the effect of EX-527 to inhibit ATX II-enhanced I_NaL (Fig. 2); (4) EX-527 inhibited the TACenhanced I_NaL (Fig. 3); (5) EX-527 ended the protracted APD and got rid of all EADs brought on by ATX II (Fig. 4); (6) EX-527 dramatically decreased the frequency and length of ATX II-induced VT and VF (Fig. 5).