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，像实验性缺血预处理（PC）。我们研究了这种保护的潜在下游介质，与PC相比。此外，PC保护心肌高能磷酸盐代谢产物（HEP）和细胞内pH值（pHi）在随后的持续缺血。活性氧（ROS）的产生可能是介导PC所必需的，我们使用开胸猪模型在体内检测了在PC方案期间抑制ROS产生的效果。磷脂酶C（PLC）是否参与了轻乙醇的心脏保护作用？豚鼠灌服2.5%乙醇16周后，用Langendorff装置进行全脑缺血再灌注。动物心脏 ...更多信息 当与对照相比时，墨水乙醇显示出改善的功能恢复和减少的肌细胞损伤。PLC封锁与U-73122取消了乙醇消费提供的保护。这些研究结果表明，长期轻度饮酒可减少心肌缺血再灌注损伤，而PLC对乙醇的心脏保护作用是必需的。长期少量饮酒的这种心脏保护作用与PC相似，可能部分解释了少量饮酒对心脏健康的有益作用2。PC是否由PC方案期间产生的活性氧介导？PC在随后的持续缺血期间保护心肌HEP和细胞内pHi。31 P-NMR数据与使用电子显微镜的心肌细胞超微结构变化相关。开胸猪进行60分钟的左前降支冠状动脉闭塞。PC是通过单次5分钟闭塞和5分钟再灌注引起的。PC+MPG组和PC组于PC前30 min开始分别输注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40 min。PC后，ATP和pHi通过25分钟的缺血和磷酸肌酸通过20分钟的缺血显着保存。通过用MPG抑制ROS产生来消除HEP和pHi的这种保存。电镜观察显示，PC保存HEP可减少心肌细胞超微结构损伤，包括减少心肌细胞肿胀、肌原纤维破坏和核染色质边缘化。这些结果表明，轻酒精的心脏保护作用可作为慢性缺血预处理用于临床应用。

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