激活乙醛脱氢酶2抑制糖尿病小鼠心肌羰基应激和缺血/再灌注损伤

Acetaldehyde dehydrogenase 2 inhibits protein oxidative damage and myocardial ischemia-reperfusion injury in diabetic mice

目的:观察乙醛脱氢酶2(ALDH2)激动剂Alda-1对Ⅰ型糖尿病(DM)小鼠心肌缺血/再灌注(I/R)损伤的影响,探讨羰基应激在DM心脏缺血性损伤易感性增高中的作用。方法:以C57BL/6雄性小鼠为实验对象,腹腔注射链脲佐菌素(STZ)制备Ⅰ型DM小鼠模型。将正常C57BL/6小鼠(20只)和DM小鼠(20只)随机分为I/R组和I/R+Alda-1治疗组,每组10只。采用冠状动脉左前降支结扎缺血30 min再灌注4 h建立在体小鼠急性心肌I/R模型,于再灌注前5 min经静脉以2 ml/(kg·h)速度分别输注生理盐水(NS)或Alda-1(16 mg/kg)并持续到再灌注结束。再灌注结束后取血检测血清乳酸脱氢酶(LDH)水平,取心肌组织检测ALDH2活性、心肌内活性氧簇(ROS)水平,蛋白羰基化程度和心肌梗死(MI)面积。结果:检测心肌ALDH2活性显示,DM小鼠心肌ALDH2活性较对照组显著降低。与对照组相比,DM小鼠心肌I/R损伤显著加重,表现为MI面积增大,血清LDH水平显著增加(均P<0.05)。再灌注期Alda-1治疗可有效提高DM小鼠I/R心肌ALDH2活性(P<0.05),并显著抑制DM小鼠的上述心肌I/R损伤(均P<0.05)。DM组I/R心肌中蛋白质羰基化程度和ROS生成较对照组I/R心肌显著增加(均P<0.05)。Alda-1治疗可有效改善DM小鼠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DM小鼠心肌抗I/R损伤能力,其机制可能与减轻DM小鼠在I/R过程中导致的蛋白质氧化损伤有关。

AIM： To investigate the protective effect of acetaldehyde dehydrogenase 2 （ALDH2） agonist Alda-1 in diabetic mice after myocardial I/R injury. METHODS： Twenty diabetic mice were random- ized into I/R group （I/R） and Alda-1 group （ I/R ＋ Alda）. Another 20 C57BL/6 mice served as normal controls. Acute myocardial I/R mouse model was established by ligation of the left anterior descending artery for 30 min followed by reperfusion for 4 h. Alda-1 （ 16 mg/kg） and normal saline at the same volume were intravenously infused at a flow rate of 2 mL/kg/h into the corresponding mice 5 rain before reperfusion. At the end of the 4-h reperfusion, ALDH2 activity, reactive oxygen species （ROS） production, and protein carbonylation in the myocardial tissue were measured. Serum level of lactate dehydrogenase （LDH） was also measured and compared. RESULTS： A significant decrease in ALDH2 activity was observed in the diabetic hearts, but this effect was blocked by Alda-1. Compared with that in control hearts, myocardial L/R injury was significantly aggravated in diabetic hearts, which was evidenced by increased serum level of LDH and infarct size （P 〈 0. 05 ）. ALDH2 activator infusion during reperfusion effectively suppressed the above-mentioned ischemic injury in the diabetic hearts （ P 〈 0. 05 ）. Furthermore, protein carbonylation and ROS production in the myocardium increased in the diabetic hearts compared with those in the control hearts （ P 〈 0. 05 ）, which was attenuated by Alda-1 treatment. CONCLUSION： Activating myocardial ALDH2 significantly improves the resistance ability against myocardial L/R injury in diabetic hearts. ALDH2-induced cardiac protection may result from suppressing myocardial L/R-induced protein oxidative damage.