Yamazaki Katrina Go, Andreyev Aleksander Y, Ortiz-Vilchis Pilar, Petrosyan Susanna, Divakaruni Ajit S, Wiley Sandra E, De La Fuente Christine, Perkins Guy, Ceballos Guillermo, Villarreal Francisco, Murphy Anne N
California State University Los Angeles, Department of Biological Sciences, Los Angeles, CA, United States; University of California San Diego, United States.
Department of Pharmacology, La Jolla, CA, United States.
Int J Cardiol. 2014 Aug 1;175(2):297-306. doi: 10.1016/j.ijcard.2014.05.009. Epub 2014 May 15.
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 week 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 h 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 1h 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.
在缺血/再灌注（IR）期间靶向线粒体可提供心脏保护作用，从而改善临床结果。评估了（-）-表儿茶素（EPI）在IR期间通过调节线粒体功能发挥心脏保护作用的潜力。
通过闭塞大鼠左前降支冠状动脉45分钟，然后分别再灌注1小时、48小时或3周来诱导缺血。单剂量组在再灌注前15分钟静脉注射EPI（10mg/kg），双剂量组在12小时后再次注射。对照组给予水。实验还使用了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小时时使梗死面积减少27%，在3周时减少28%。双剂量治疗在48小时时使梗死面积进一步减少80%，在3周时减少52%。再灌注1小时后，EPI对线粒体功能的保护作用明显，此时线粒体显示出较少的呼吸抑制、较低的线粒体Ca2+负荷以及与较高组织ATP水平相关的NADH储备。在NRVM中的机制研究表明，EPI可急性刺激最大呼吸速率，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可阻断这一作用。在成肌细胞中，线粒体丙酮酸载体成分的敲低可阻断EPI诱导的呼吸刺激。
静脉注射EPI可能通过增强底物供应来维持线粒体功能，从而发挥心脏保护作用。这些引人注目的结果揭示了一种天然产物具有潜在临床应用价值的新机制。
