Correction of Defective Interdomain Interaction Within Ryanodine Receptor by Antioxidant Is a New Therapeutic Strategy Against Heart Failure

Abstract

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 (EVϩ), but not in the untreated paced dogs (EVϪ), normal cardiac function was restored almost completely. In the SR vesicles isolated from the EVϪ, oxidative stress of the RyR2 (reduction in the number of free thiols) was severe, but it was negligible in EVϩ. The oxidative stress of the RyR2 destabilized interdomain interactions within the RyR2 (EVϪ), but its effect was reversed in EVϩ. Abnormal Ca 2ϩ leak through the RyR2 was found in EVϪ but not in EVϩ. The amount of the RyR2-bound FKBP12.6 was less in EVϪ than in normal dogs, whereas it was restored almost to a normal amount in EVϩ. 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 Ca 2ϩ leak. Both cell shortening and Ca 2ϩ 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 Ca 2ϩ leak and LV remodeling, leading to an improvement of cardiac function and an attenuation of LV remodeling.

Deficient ryanodine receptor S -nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes

“…In a canine model of heart failure, an increase in RyR oxidation and Ca 2ϩ leak was observed and corrected by antioxidant treatment (32). In this sense, S-nitrosylation may prevent oxidation of reactive thiols of the channel, which is known to induce cross-linking between the subunits of RyR and increase the open probability of the channel, and NO is able to prevent this modification (33).…”

NADPH oxidase signaling and cardiac myocyte function

“…Multiple mechanisms contribute to myocardial dysfunction including altered excitation-contraction coupling, impaired myofilament calcium responsiveness, mitochondrial dysfunction and energy deficit, extracellular matrix remodeling and the loss of myocytes. A significant body of evidence implicates oxidative stress in the development of contractile dysfunction through one or more of these mechanisms [77], [78], [79], [80], [81], [82], [83] and [84], but the potential role of NADPH oxidase-derived ROS remains to be established.…”

Redox Sensitivity of the Ryanodine Receptor Interaction with FK506-binding Protein

“…Elevated catecholamine levels produce reactive oxygen species due to autoxidation, leading to cardiomyopathy as well as age-related neurodegeneration (62,64,66). It is noteworthy that a recent study reported on reduced RyR2-FKBP12.6 association in an animal model of heart failure that was corrected with the administration of an antioxidant (67).…”