激活乙醛脱氢酶2抑制老年大鼠心肌缺血再灌注损伤

Acetaldehyde dehydrogenase 2 activation inhibits myocardial ischemia-reperfusion injury in senescent rats

摘要:

目的 衰老心肌对缺血/再灌注（I/R）损伤的耐受能力显著降低，导致老年心肌缺血易损性。本研究旨在探讨乙醛脱氢酶2（ALDH2）激动剂Alda-1对老年大鼠心肌I/R损伤的影响。方法 成年（3～4月龄，40只）和老年（22～24月龄，40只）雄性SD大鼠随机分为I/R组和I/R+Alda-1治疗组。采用冠状动脉左前降支结扎缺血30min再灌注4h建立在体大鼠急性心肌I/R模型，于再灌注前5min经静脉分别以2ml/（kg·h）速度分别输注生理盐水（0.9% NaCl）和Alda-1（16mg/kg）并持续到再灌注结束。于术中监测血流动力学指标，再灌注结束后取心肌组织检测ALDH2活性、蛋白质羰基化程度和心肌内活性氧簇（ROS）水平，抽取血样检测LDH水平。结果 检测心肌ALDH2活性显示，老年心肌ALDH2活性较成年组显著降低。与成年组相比，老年心肌缺血再灌注损伤显著加重，表现为心肌收缩舒张速率显著降低，血清乳酸脱氢酶（LDH）水平显著增加（均P＜0.05）。再灌注期Alda-1治疗可有效提高老年I/R心肌ALDH2活性（P＜0.05），并显著抑制老年大鼠的上述心肌缺血再灌注损伤（均P＜0.05）。老年组I/R心肌中蛋白质羰基化程度和ROS生成较成年I/R心肌显著增加（均P＜0.05）。Alda-1治疗可有效改善老年I/R心肌中的蛋白质羰基化和ROS水平。结论 激活心肌ALDH2可显著改善衰老心肌抗I/R损伤能力，其机制可能与减轻I/R导致的蛋白质氧化损伤有关。

Abstract:

Objective Aging heart shows significantly reduced tolerance to myocardial ischemia/reperfusion (I/R) injury, so senescent heart is prone to be damaged by the injury. This study was designed to investigate the protective effect of acetaldehyde dehydrogenase 2 (ALDH2) agonist Alda-1 in aging rats after myocardial I/R injury. Methods A total of 40 aging male Sprague Dawley (SD) rats (at an age of 20 to 22 months) were randomized into I/R group (I/R) and Alda-1 group (I/R＋Alda). Another 40 adult rats at an age of 3 to 4 months served as adult control. Rat acute myocardial I/R model was established by ligation of left anterior descending artery for 30min followed by reperfusion for 4h. Alda-1(16mg/kg) and normal saline at the same volume were intravenously infused at a flow rate of 2ml/(kg·h) into the left ventricle of corresponding rats in 5min before reperfusion. The left ventricular pressure was monitored at the same time. At the end of 4 hours reperfusion, ALDH2 activity, reactive oxygen species (ROS) production, and protein carbonylation in the myocardial tissue were measured. Serum level of lactate dehydrogenase (LDH) was tested. Results A significant decrease in ALDH2 activity was observed in the aging hearts, but this effect was blocked by Alda-1. Compared with the adult hearts, myocardial I/R injury was significantly aggravated in aging hearts, which were evidenced by reduced±LVdP/dtmax and increased serum level of LDH (P＜0.05). ALDH2 activator infusion during reperfusion effectively suppressed the above mentioned ischemic injury in the aging hearts (P＜0.05). Furthermore, protein carbonylation and ROS production in the myocardium were increased in the aging hearts compared with the adult hearts (P＜0.05), which was attenuated by Alda-1 treatment. Conclusion Activating myocardial ALDH2 significantly improves the resistance ability to myocardial I/R injury in aging heart. ALDH2-induced cardiac protection may be through suppressing myocardial I/R-induced protein oxidative damage.