Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure

Background - Defective interdomain interaction within the ryanodine receptor ( RyR2) seems to play a key role in the pathogenesis of heart failure, as shown in recent studies. In the present study we investigated the effect of oxidative stress on the interdomain interaction, its outcome in the cardiac function in heart failure, and the possibility of preventing the problem with antioxidants. Methods and Results - Sarcoplasmic reticulum ( SR) vesicles were isolated from dog left ventricular ( LV) muscle ( normal or rapid ventricular pacing for 4 weeks with or without the antioxidant edaravone). In the edaravone- treated paced dogs ( EV +), but not in the untreated paced dogs ( EV -), normal cardiac function was restored almost completely. In the SR vesicles isolated from the EV -, oxidative stress of the RyR2 ( reduction in the number of free thiols) was severe, but it was negligible in EV +. The oxidative stress of the RyR2 destabilized interdomain interactions within the RyR2 ( EV -), but its effect was reversed in EV +. Abnormal Ca2+ leak through the RyR2 was found in EV - but not in EV +. The amount of the RyR2- bound FKBP12.6 was less in EV - than in normal dogs, whereas it was restored almost to a normal amount in EV +. The NO donor 3- morpholinosydnonimine ( SIN- 1) reproduced, in normal SR, several abnormal features seen in failing SR, such as defective interdomain interaction and abnormal Ca2+ leak. Both cell shortening and Ca2+ transients were impaired by SIN- 1 in isolated normal myocytes, mimicking the pathophysiological conditions in failing myocytes. Incubation of failing myocytes with edaravone restored the normal properties. Conclusions - During the development of heart failure, edaravone ameliorated the defective interdomain interaction of the RyR2. This prevented Ca2+ leak and LV remodeling, leading to an improvement of cardiac function and an attenuation of LV remodeling.