Intravenous (-)-epicatechin reduces myocardial ischemic injury by protecting mitochondrial function.
Intravenous (-)-epicatechin reduces myocardial ischemic injury by protecting mitochondrial function.
复制标题
DOI：
10.1016/j.ijcard.2014.05.009
复制
发表时间：
2014-08-01
影响因子：
3.5
通讯作者：
Murphy AN
中科院分区：
文献类型：
--
作者：
Yamazaki KG;Andreyev AY;Ortiz-Vilchis P;Petrosyan S;Divakaruni AS;Wiley SE;De La Fuente C;Perkins G;Ceballos G;Villarreal F;Murphy AN
在缺血/再灌注（IR）期间靶向线粒体可以提供心脏保护，从而改善临床结果。评价了IR期间（−）-表儿茶素（EPI）通过调节线粒体功能的心脏保护潜力。通过阻断大鼠冠状动脉左前降支45分钟，然后再灌注1小时、48小时或3周（wk）诱导缺血。单剂量组在再灌注前15 min静脉注射EPI（10 mg/kg），双剂量组在再灌注后12 h静脉注射EPI（10 mg/kg）。对照组接受水。实验还利用培养的新生大鼠心室肌细胞（NRVM）和成肌细胞。单剂量的EPI在48小时和3周时分别使梗死面积减少了27%和28%。双剂量治疗进一步减少梗死面积的80%，在48小时，52%，3周。再灌注1小时后，EPI对线粒体功能的保护作用是明显的，此时线粒体表现出较少的呼吸抑制，较低的线粒体Ca 2+负荷，以及与较高的组织ATP水平相关的保存的NADH池。NRVM的机制研究表明，EPI急性刺激最大呼吸速率，这种作用被线粒体丙酮酸载体，一氧化氮合酶或可溶性鸟苷酸环化酶的抑制剂阻断。在成肌细胞中，线粒体丙酮酸载体的组分的敲低阻断EPI诱导的呼吸刺激。IV EPI通过保护线粒体功能赋予心脏保护作用，这可能是通过增强底物供应实现的。这些挑衅性的结果证明了一种具有潜在临床实用性的天然产物的新机制。
Targeting the mitochondria during ischemia/reperfusion (IR) can confer cardioprotection leading to improved clinical outcomes. The cardioprotective potential of (−)-epicatechin (EPI) during IR via modulation of mitochondrial function was evaluated. Ischemia was induced in rats via a 45 min occlusion of the left anterior descending coronary artery followed by 1 h, 48 h, or 3 weeks (wk) reperfusion. EPI (10 mg/kg) was administered IV 15 min prior to reperfusion for the single dose group and again 12 h later for the double dose group. Controls received water. Experiments also utilized cultured neonatal rat ventricular myocytes (NRVM) and myoblasts. A single dose of EPI reduced infarct size by 27% at 48 hours and 28% at 3 week. Double dose treatment further decreased infarct size by 80% at 48 h, and 52% by 3 weeks. The protective effect of EPI on mitochondrial function was evident after 1 hr of reperfusion when mitochondria demonstrated less respiratory inhibition, lower mitochondrial Ca2+ load, and a preserved pool of NADH that correlated with higher tissue ATP levels. Mechanistic studies in NRVM revealed that EPI acutely stimulated maximal rates of respiration, an effect that was blocked by inhibitors of the mitochondrial pyruvate carrier, nitric oxide synthase, or soluble guanylyl cyclase. In myoblasts, knockdown of components of the mitochondrial pyruvate carrier blocked EPI-induced respiratory stimulation. IV EPI confers cardioprotection via preservation of mitochondrial function potentially through enhanced substrate provision. These provocative results document a novel mechanism of a natural product with potential clinical utility.