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

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 (INaL) in ventricular myocytes; reduction of INaL is a novel target for heart failure therapy. Deacetylase SIRT1 has a variety of cardioprotective effects, but whether it exerts antiarrhythmic effects by inhibiting INaL remains to be studied. In previous experiments, it was found that SRT2104, a specific agonist of SIRT1, could inhibit INaL 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 INaL, but there was no study of INaL 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 INaL 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 INaL (Fig. 1 A, B); (2) The inhibition of ATX II-enhanced INaL 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 INaL (Fig. 2); (4) EX-527 inhibited the TACenhanced INaL (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).