Signal Transduction in the Cardioprotective Effect of Light Alcohol and its clinical application for ischemic preconditioning

流行病学研究表明，轻度至中度使用乙醇与预防致命性冠状动脉疾病的保护作用有关。我们发现乙醇的心脏保护作用需要腺苷A1受体在缺血时激活，就像实验性缺血预处理（PC）一样。我们研究了这种保护的潜在下游介质，并与PC进行了比较。此外，PC在随后的持续缺血中保持心肌高能磷酸盐代谢物（HEP）和细胞内pH （pHi）。活性氧（ROS）的产生可能需要介导PC，我们使用开胸猪模型研究了在PC方案中抑制ROS产生的影响。磷脂酶C （PLC）是否参与轻乙醇的心脏保护作用？取灌胃2.5%乙醇16周的豚鼠心脏，采用Langendorff仪进行全身缺血再灌注。与对照组相比，更多的乙醇显示出功能恢复的改善和心肌细胞损伤的减少。PLC用U-73122封锁，取消了乙醇消耗提供的保护。这些发现表明，长期少量饮酒可减少心肌缺血-再灌注损伤，乙醇的这种心脏保护作用需要PLC。长期少量饮酒对心脏的保护作用类似于PC，这可能部分解释了少量饮酒对心脏健康的有益影响。PC是由在PC协议中产生的活性氧介导的吗？PC在随后的持续缺血中保留心肌HEP和细胞内pHi。电镜观察了31P-NMR数据与心肌细胞超微结构变化的相关性。开胸猪接受左冠状动脉前降支闭塞60分钟。单次5分钟闭塞和5分钟再灌注诱发PC。细胞扩散性自由基清除剂、N-2-巯基丙酰甘氨酸（MPG）或安慰剂生理盐水于PC前30分钟开始输注40分钟（PC+MPG组和PC组）。缺血25 min后，ATP和pHi显著保留，缺血20 min后，磷酸肌酸显著保留。通过MPG抑制ROS的产生，HEP和pHi的保存被消除。电镜显示，用PC保存HEP与超微结构损伤减少有关，包括心肌细胞肿胀、肌纤维断裂和核染色质边缘减少。这些结果表明，轻酒精的心脏保护作用可以作为慢性缺血预处理的临床应用

Epidemiologic studies have shown that light to moderate ethanol use is associated with a protective effect against fatal coronary artery disease. We showed that the cardioprotective effect of ethanol requires adenosine A1 receptor activation at the time of ischemia, like experimental ischemic preconditioning(PC). We investigated the potetial downstream mediators of this protection, compared with PC. Furthermore, PC preserves myocardial high-energy phosphate metabolites (HEP) and intracellular pH (pHi) during subsequent sustained ischemia. Reactive oxygen species (ROS) generation may be required to mediate PC, we examined the effects of inhibiting ROS generatio during a PC protocol in vivo using an open-chest porcine model.1. Is phospholipase C (PLC) involved in the cardioprotective effect of light ethanol?Hearts were isolated from guinea pigs after drinkng 2.5% ethanol for 16 weeks and were subjected to global ischemia and reperfusion using Langendorff apparatus. Hearts from animals dr … More inking ethanol showed improved functional recovery and decreased myocyte damage when compared with controls. PLC blockade with U-73122 abolished the protection provided by ethanol consumption. These findings indicate that long-term light alcohol consumption reduces myocardial ischemia-reperfusion injury and that PLC is required for this cardioprotective effect of ethanol. This cardioprotective effect of long-term light alcohol consumption mimics PC and may, in part, account for the beneficial effect of light drinking on cardiac health2. Is PC mediated by reactive oxygen species produced during PC protocol?PC preserves myocardial HEP and intracellular pHi during subsequent sustained ischemia. 31P-NMR data was correlated with myocyte ultrastructural changes using electron microscopy. Open chest pigs underwent 60 minutes of left anterior descending coronary artery occlusion. PC was elicited by a single episode of 5-minute occlusion and 5-minute reperfusion. The cell diffusible free radical scavenger, N-2- mercaptopropionyl glycine (MPG) or placebo saline were infused for 40 minutes starting 30 minutes before PC (PC+MPG group ＆ PC group). Following PC, ATP and pHi were significantly preserved through 25 min of ischemia and phosphocreatine through 20 min of ischemia. This preservation of HEP and pHi was abolished by inhibiting ROS generation with MPG. HEP preservation with PC was associated with reduced ultrastructural damage as demonstrated by electron microscopy, including less myocyte swelling, myofibrillar disruption and nuclear chromatin marginationThese results suggest that the cardioprotective effect of light alcohol can be used for clinical application as a chronic ischemic preconditioning Less