MCU Overexpression Rescues Inotropy and Reverses Heart Failure by Reducing SR Ca(2+) Leak.
MCU Overexpression Rescues Inotropy and Reverses Heart Failure by Reducing SR Ca(2+) Leak.
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MCU过表达通过减少SR Ca（2+）泄漏挽救肌力变性和逆转心力衰竭。
DOI：
10.1161/circresaha.120.318562
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发表时间：
2021-04-16
影响因子：
20.1
通讯作者：
O'Rourke B
中科院分区：
文献类型：
--
作者：
Liu T;Yang N;Sidor A;O'Rourke B
在心力衰竭（HF）中，受损的肌浆网（SR）Ca 2+释放和胞质Na+过载抑制线粒体Ca 2+（mCa 2+）信号传导，导致维持基质NAD（P）H氧化还原电位的能力降低，导致工作负荷增加时氧化应激增加。增加mCa 2+可以逆转这种缺陷，但可能会增加线粒体Ca 2+超载的可能性。确定中度线粒体钙单向转运体（MCU）过表达对豚鼠HF和心源性猝死模型（ACi）中HF和偶发性心律失常的发生是否具有有益或有害影响。体内病毒基因转移用于将ACi心脏中的MCU水平增加约30%。与来自ACi心脏的肌细胞相比，来自MCU过表达的心脏（ACi+MCU）的左心室肌细胞显示增强的mCa 2+摄取、降低的氧化应激、以及增加的β-肾上腺素能和频率依赖性Ca 2+瞬变和收缩增强。MCU过表达减少了ACi组SR Ca 2+泄漏，减轻了HF中兰尼碱受体二硫键交联的升高。β-肾上腺素能反应在离体灌注ACi心脏中减弱，并且这些缺陷在ACI+MCU心脏中正常化。为了检查MCU过表达的体内作用，在心脏失代偿开始时，在主动脉收缩后2- 3周用MCU病毒转导ACi心脏。两周后，未治疗ACi组的心功能恶化（缩短分数：2 w为39±1%，4 w为32±1%），而MCU过表达显著改善心功能（2 w为36±1%，4 w为42±2%）。失代偿的ACi心脏中MCU的过度表达还可以减轻肺水肿和间质纤维化并预防触发的心律失常。衰竭心脏中的中度MCU过表达通过抑制线粒体氧化应激诱导的SR Ca 2+渗漏增强了离体肌细胞和灌注心脏中的收缩性和对β-肾上腺素能刺激的反应。MCU过表达也逆转HF和抑制异位室性心律失常。
In heart failure (HF), impaired sarcoplasmic reticulum (SR) Ca2+ release and cytosolic Na+ overload depress mitochondrial Ca2+ (mCa2+) signaling, resulting in a diminished ability to maintain matrix NAD(P)H redox potential, leading to increased oxidative stress when workload increases. Enhancing mCa2+ can reverse this defect but could potentially increase the likelihood of mitochondrial Ca2+ overload. To determine if moderate mitochondrial Ca2+ uniporter (MCU) overexpression has beneficial or detrimental effects on the development of HF and incident arrythmias in a guinea pig model (ACi) of HF and sudden cardiac death. In vivo viral gene transfer was used to increase MCU levels by ~30% in ACi hearts. Left ventricular myocytes from hearts with MCU overexpression (ACi+MCU) displayed enhanced mCa2+ uptake, decreased oxidative stress, and increased β-adrenergic- and frequency-dependent augmentation of Ca2+ transients and contractions, compared to myocytes from ACi hearts. MCU overexpression decreased SR Ca2+ leak in the ACi group and mitigated the elevated ryanodine receptor disulfide crosslinks in HF. β-adrenergic responses were blunted in isolated perfused ACi hearts and these deficiencies were normalized in ACI+MCU hearts. To examine the in vivo effects of MCU overexpression, ACi hearts were transduced with the MCU virus 2–3w after aortic constriction, at the onset of cardiac decompensation. Two weeks later, cardiac function worsened in the untreated ACi group (fractional shortening: 39±1% at 2w and 32±1% at 4w), whereas MCU overexpression significantly improved cardiac function (36±1% at 2w and 42±2% at 4w). MCU overexpression in the decompensating ACi heart also attenuated pulmonary edema and interstitial fibrosis and prevented triggered arrhythmias. Moderate MCU overexpression in failing hearts enhances contractility and responses to β-adrenergic stimulation in isolated myocytes and perfused hearts by inhibiting mitochondrial oxidative stress-induced SR Ca2+ leak. MCU overexpression also reversed HF and inhibited ectopic ventricular arrhythmias.