Abstract: 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 randomized 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 min 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 I/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 I/R injury in diabetic hearts. ALDH2-induced cardiac protection may result from suppressing myocardial I/R-induced protein oxidative damage.