To investigate the protective effect of dimethyl fumarate (DMF) on myocardial ischemia/reperfusion (MI/R) injury in diabetic rats by regulating the nuclear factor E2-related factor 2 (Nrf2).

Sixty Sprague-Dawley rats were fed with a high-fat diet for 4 weeks. After fasting for 12 h, 1% streptozotocin citrate buffer solution was injected intraperitoneally for 25 mg/kg to prepare a diabetic rat model, and then a MI/R injury model was prepared after high-fat feeding for 4 weeks. These 60 diabetic rats were divided into a sham operation group (S group), a diabetes with MI/R group (MI/R group), a DMF + MI/R group (R group) and a DMF + ML385 + MI/R group (RE group), 15 rats in each group. Rats in the R and RE groups were given DMF (25 mg/kg) by intragastrical administration once a day for 7 d, and rats in the S and MI/R groups were given isosmotic NaCl solution in equal volume. Then rats in the RE group were injected intraperitoneally with the Nrf2 inhibitor ML385 (30 mg/kg) 30 min before ischemia. Rats in the MI/R, R and RE groups were ligated with the left anterior descending coronary artery for 30 min, and then restored perfusion for 120 min to prepare the MI/R model. Rats in the S group only opened the chest without ligating the coronary artery. The levels of myocardial infarction area, heart rate, left ventricular systolic pressure (LVSP), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), lactate dehydrogenase (LDH), creatine kinase isoenzyme-MB (CK-MB), cardiac troponin I (cTnI), malondialdehyde, reactive oxygen species (ROS), superoxide dismutase (SOD) and the protein levels of Nrf2, heme oxygenase-1 (HO-1) were compared among the four groups.

No myocardial infarction occurred in the S group. The myocardial infarction area in the MI/R, R and RE groups showed statistically significant differences [(32.5 ± 2.2)%, (23.2 ± 1.6)%, (29.5 ± 1.7)%; F = 98.364, P < 0.001], and it was significantly higher in the MI/R and RE groups than in the R group (both P < 0.05). There were significant differences in the levels of heart rate, LVSP, LVEF, LVFS, LDH, CK-MB, cTnI, malondialdehyde, ROS, SOD and the protein levels of Nrf2, HO-1 in the four groups (F = 198.124, 103.884, 86.052, 39.256, 109.126, 164.241, 98.673, 132.102, 108.146, 76.535, 61.132, 120.401; all P < 0.001). Further pairwise comparison revealed that compared with the S group, the levels of heart rate [(404 ± 30), (264 ± 27), (331 ± 22), (270 ± 23) beats/min], LVSP [(127 ± 19), (73 ± 17), (98 ± 10), (80 ± 10) mmHg], LVEF [(68.1 ± 3.2)%, (39.5 ± 4.5)%, (48.4 ± 1.9)%, (38.6 ± 2.3)%], LVFS [(32.4 ± 1.2)%, (18.5 ± 0.8)%, (25.6 ± 0.7)%, (20.6 ± 1.1)%] and SOD were decreased significantly, while the levels of LDH [(0.21 ± 0.04), (0.54 ± 0.07), (0.37 ± 0.06), (0.52 ± 0.08) U/mg], CK-MB [(1 783 ± 41), (4 357 ± 523), (3 068 ± 276), (4 198 ± 490) ng/L], cTnI [(406 ± 45), (1 437 ± 251), (748 ± 167), (1 520 ± 190) ng/L], malondialdehyde, ROS and the protein levels of Nrf2, HO-1 were increased significantly in the MI/R, R and RE groups (all P < 0.05). As compared with the R group, the levels of heart rate, LVSP, LVEF, LVFS, SOD and the protein levels of Nrf2, HO-1 were decreased significantly, while the levels of LDH, CK-MB, cTnI, malondialdehyde and ROS were increased significantly in the MI/R and RE groups (all P < 0.05).

DMF can reduce MI/R injury in diabetic rats by regulating Nrf2 and thus exert its myocardial protective effect.