Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure
Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure
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DOI：
10.1016/j.jacc.2007.01.064
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发表时间：
2007-04-24
影响因子：
24
通讯作者：
Matsuzaki, Masunori
中科院分区：
文献类型：
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作者：
Mochizuki, Mamoru;Yano, Masafumi;Matsuzaki, Masunori
在心力衰竭中，兰尼碱受体（RyR）的N-末端和中央结构域之间的相互作用是有缺陷的，在儿茶酚胺能多态性室性心动过速（CPVT）患者中发现了许多突变，方法从犬左心室肌分离肌浆网囊泡（正常或快速心室起搏4周）。结果卡维地洛处理后的犬（CV+）心功能正常，而未处理的犬（CV-）心功能无明显变化。在CV-中，RyR内的结构域间相互作用是有缺陷的（即，处于未拉链状态），如通过荧光猝灭技术所测定的。然而，在CV+中，结构域相互作用保持正常（即，处于拉链状态）。在CV-中，RyR的氧化应激（游离巯基数量减少）是严重的，但在CV+中可以忽略不计。在（CV-）失败的心肌细胞，孵育低剂量CV（30 nmol/1），消除细胞内活性氧，细胞缩短没有急性影响，显着改善收缩功能和Ca 2+瞬变。然而，结构域解压缩DPc 10后，CV是没有effect.Conclusions卡维地洛，在足以产生抗氧化作用的浓度，改善细胞内的Ca 2+处理和收缩功能障碍，纠正缺陷的域间相互作用内RyR在衰竭的心脏。
Objectives We investigated whether defective intracellular Ca2+ handling is corrected by carvedilol in heart failure.Background In heart failure, the interaction between the N-terminal and central domains of the ryanodine receptor (RyR), the domains where many mutations have been found in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), is defective, as shown in our recent report.Methods Sarcoplasmic reticulum vesicles were isolated from canine left ventricular muscle (normal or 4-weeks rapid ventricular pacing). The RyR was labeled with the fluorescent conformational probe methylcournarin acetate (MCA) with DPc10 (a synthetic peptide corresponding to Gly(2460)-pro(2495) of RyR, one of the mutable domains in CPVT) as a site-direction carrier.Results Normal cardiac function was well preserved in carvedilol-treated/paced dogs (CV+) but not in the untreated/ paced dogs (CV-). In CV-, the interdomain interaction within RyR was defective (i.e., in an unzipped state), as determined by the fluorescence quenching technique. However, in CV+, the domain interaction remained normal (i.e., in a zipped state). In CV-, oxidative stress of RyR (reduction in the number of free thiols) was severe, but it was negligible in CV+. In (CV-) failing cardiornyocytes, incubation with low-dose CV (30 nmol/1), which eliminated intracellular reactive oxygen species with no acute effect on cell shortening, markedly improved the contractile function and Ca2+ transient. However, after domain unzipping by DPc10, CV was without effect.Conclusions Carvedilol, at a concentration that is sufficient to produce antioxidant effect, improves the intracellular Ca2+ handling and contractile dysfunction by correcting defective interdomain interaction within the RyR in the failing heart.