探讨白藜芦醇在糖尿病心肌缺血再灌注（I/R）损伤中对转录因子E2相关因子2（Nrf2）/血红素氧合酶1（HO-1）信号通路的影响。

将2型糖尿病模型制备成功的60只大鼠分成假手术组、I/R组、白藜芦醇（R）组、白藜芦醇+ EX527（RE）组，每组各15只。采用结扎左冠状动脉前降支30 min、恢复灌注120 min的方法制备心肌I/R损伤模型。R组及RE组大鼠于术前7 d连续腹腔注射白藜芦醇15 mg/kg，假手术组及I/R组大鼠腹腔注射等容量的等渗NaCl溶液，RE组大鼠于缺血前15 min尾静脉注射EX527 1 μg/kg。于再灌注120 min末，采用酶联免疫吸附测定法检测血清乳酸脱氢酶（LDH）及肌酸激酶同工酶（CK-MB）。随后处死大鼠取心肌组织，采用苏木素-伊红（HE）染色观察心肌病理学变化，采用2，3，5-氯化三苯基四氮唑法检测心肌梗死面积百分比，并检测心肌组织丙二醛含量及超氧化物歧化酶（SOD）活性。采用Western-blotting法检测各组大鼠心肌沉默信息调节因子1（SIRT1）、Nrf2及HO-1蛋白表达水平。

HE染色可见，假手术组大鼠心肌细胞轻度断裂、水肿，少量炎症细胞浸润；I/R组大鼠心肌纤维排列杂乱，心肌间质充血水肿伴大量炎症细胞浸润；R组大鼠心肌组织结构相对整齐，偶见核固缩；RE组大鼠心肌纤维排列杂乱，核固缩现象明显，炎症细胞浸润明显。假手术组大鼠无心肌梗死发生，I/R组大鼠心肌梗死面积占比为（51 ± 6）%，R组大鼠占比为（37 ± 4）%，RE组大鼠占比为（41 ± 3）%，各组间比较差异有统计学意义（F = 160.703，P < 0.001），R组及RE组大鼠心肌梗死的占比面积均显著小于I/R组大鼠，且R组大鼠心肌梗死面积的占比更小（P均<0.05）。各组大鼠血清LDH、CK-MB、丙二醛、SOD、SIRT1、Nrf2及HO-1表达水平比较，差异均有统计学意义（F = 144.101、158.545、53.682、99.273、50.121、59.153、143.702，P均< 0.001）。进一步两两比较发现，与假手术组比较，I/R组、R组、RE组大鼠的LDH、CK-MB及丙二醛含量均显著升高，SOD活性、SIRT1、Nrf2及HO-1蛋白表达水平均显著降低（P均<0.05）；与I/R组比较，R组及RE组大鼠的LDH、CK-MB及丙二醛含量均显著降低，SOD活性、SIRT1、Nrf2及HO-1蛋白表达水平均显著升高，且LDH、CK-MB及丙二醛含量在R组大鼠更低，SOD活性、SIRT1、Nrf2及HO-1蛋白表达水平在R组大鼠更高（P均<0.05）。

白藜芦醇可通过促进SIRT1激活Nrf2/HO-1信号通路来减轻2型糖尿病大鼠心肌的氧化应激反应及心肌I/R损伤。

To investigate the effect of resveratrol on the nuclear factor-E2 related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway in myocardial ischemia-reperfusion (I/R) injury of type 2 diabetes mellitus rats.

Sixty Sprague-Dawley rats with type 2 diabetes mellitus were randomly divided into a sham operation group, a I/R group, a resveratrol preconditioning (R) group, and a resveratrol preconditioning + EX527 (RE) group, 15 rats in each group. Myocardial I/R injury was produced by ligating the left coronary anterior descending artery for 30 min followed by 120 min reperfusion. Rats in the R group and RE group were intraperitoneally injected with resveratrol (15 mg/kg, once a day) for 7 days before the operation; rats in the sham operation group and I/R group were intraperitoneally injected with the equal capacity of isotonic NaCl solution; rats in the RE group also received EX527 (1 μg/kg) by caudal vein injection at 15 min before ischemia. At the end of 120 min reperfusion, blood samples were taken for detecting the concentration of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) by the enzyme-linked immunosorbent assay. Then rats were sacrificed in each group; the pathological changes of myocardium were observed by hematoxylin-eosin (HE) staining and the myocardial infarct size was measured by 2,3,5-triphenyltetrazolium chloride. The levels of malondialdehyde and superoxide dismutase (SOD) were compared among the four groups. The expression levels of myocardial silent information regulator of transcription 1 (SIRT1), Nrf2, and HO-1 protein were detected using Western-blotting.

From HE staining, the myocardial cells were slightly broken and edematous, with a small amount of inflammatory cells in the sham operation group; the myocardial fibers were disorderly arranged, with myocardial interstitial congestion and edema infiltrated by a large number of inflammatory cells in the I/R group; the myocardial tissue was relatively structurally neat, with occasional karyopyknosis in the R group; the myocardial fibers were arranged in a disorderly way, with obvious karyopyknosis and inflammatory cells in the RE group. No myocardial infarction occurred in the sham operation group. The myocardial infarct size in the I/R group, R group, and RE group showed significant differences [(51 ± 6)%, (37 ± 4)%, (41 ± 3)%; F = 160.703, P < 0.001]. It was much smaller in the R group and RE group than in the I/R group, and was smallest in the R group (all P < 0.05). The levels of LDH, CK-MB, malondialdehyde, SOD, SIRT1, Nrf2, and HO-1 all showed significant differences among the four groups (F = 144.101, 158.545, 53.682, 99.273, 50.121, 59.153, 143.702; all P < 0.001). Compared with the sham operation group, the levels of LDH, CK-MB, and malondialdehyde increased obviously in the I/R group, R group and RE group, and the levels of SOD, SIRT1, Nrf2, and HO-1 decreased (all P < 0.05). Compared with the I/R group, the levels of LDH, CK-MB, and malondialdehyde decreased obviously in the R group and RE group, which decreased most in the R group, and the levels of SOD, SIRT1, Nrf2, and HO-1 increased, which increased most in the R group (all P < 0.05).

Resveratrol can alleviate oxidative stress and myocardial I/R injury in type 2 diabetes mellitus rats by promoting SIRT1 to activate the Nrf2/HO-1 signaling pathway.