Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure
Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure
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DOI：
10.1161/circulationaha.105.555623
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发表时间：
2005-12-06
期刊：
影响因子：
37.8
通讯作者：
Matsuzaki, M
中科院分区：
文献类型：
--
作者：
Yano, M;Okuda, S;Matsuzaki, M
背景：最近的研究表明，兰尼碱受体（RyR 2）内的结构域间相互作用缺陷似乎在心力衰竭的发病机制中起关键作用。在本研究中，我们调查了氧化应激的影响域间的相互作用，其结果在心脏功能在心力衰竭，并防止问题的可能性与antioxidants.Methods和Results -肌浆网（SR）囊泡分离出狗左心室（LV）肌肉（正常或快速心室起搏4周或无抗氧化剂依达拉奉）。在依达拉奉治疗的起搏犬（EV +）中，而在未治疗的起搏犬（EV -）中，正常的心脏功能几乎完全恢复。在从EV -分离的SR囊泡中，RyR 2的氧化应激（游离巯基数量减少）是严重的，但在EV +中可以忽略不计。RyR 2的氧化应激使RyR 2（EV -）内的结构域间相互作用不稳定，但其作用在EV +中被逆转。在EV -中发现了RyR 2的异常Ca 2+渗漏，而在EV +中未发现。EV -中RyR 2结合的FKBP12.6的量低于正常狗，而EV +中几乎恢复到正常量。NO供体3- morpholinosydnonimine（SIN- 1）复制，在正常SR，在失败的SR中看到的几个异常功能，如缺陷的域间相互作用和异常的Ca 2+泄漏。细胞缩短和Ca 2+瞬变受损SIN- 1在分离的正常心肌细胞，模仿失败的心肌细胞的病理生理条件。孵育失败的心肌细胞与依达拉奉恢复正常properties.Conclusions -在心力衰竭的发展过程中，依达拉奉改善了RyR 2的缺陷域间相互作用。这可以防止Ca 2+渗漏和LV重塑，从而改善心脏功能并减弱LV重塑。
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.