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目的:探讨组蛋白去乙酰化酶(HDAC)抑制剂(TSA)对糖尿病大鼠心肌缺血再灌注(MI/R)损伤是否具有保护作用及其机制。方法:SD大鼠腹腔注射链脲佐菌素(STZ)建立糖尿病大鼠模型,饲养8周。大鼠麻醉后行机械通气,结扎冠状动脉左前降支(LAD)30 min随后开放120 min以建立心肌缺血再灌注模型。TTC和Evens blue双重染色法测定梗死面积,TUNEL染色检测心肌凋亡程度,免疫印迹法检测蛋白激酶B(Akt)和糖原合酶激酶-3β(Gsk3β)的磷酸化水平以及凋亡相关蛋白Bcl-2,Bax的表达量。结果:HDAC抑制剂能够降低糖尿病大鼠的心肌梗死面积,减轻MI/R损伤所致心肌凋亡;合并给予Akt抑制剂后,TSA的保护作用被抑制;进一步研究表明HDAC抑制剂提高了高糖状态下MI/R损伤后的心肌Akt磷酸化水平,同时也提高了Akt下游蛋白p-Gsk3β的表达量。结论:Akt的激活是HDAC抑制剂发挥糖尿病MI/R损伤保护作用的关键机制,HDAC抑制剂可能是通过Akt/Gsk3β信号通路发挥保护作用。
Objective: To investigate whether histone deacetylase (HDAC) inhibitor (TSA) has a protective effect on myocardial ischemia-reperfusion (MI / R) injury in diabetic rats and its mechanism. Methods: SD rats were intraperitoneally injected with streptozotocin (STZ) to establish a diabetic rat model for 8 weeks. Rats were anesthetized and then mechanically ventilated. Left anterior descending coronary artery (LAD) was ligated for 30 min and then opened for 120 min to establish myocardial ischemia-reperfusion model. TTC and Evens blue staining were used to determine the infarction area. TUNEL staining was used to detect the degree of myocardial apoptosis. The phosphorylation of Akt and Gsk3β was detected by Western blotting, and the apoptosis-related protein Bcl -2, Bax expression. Results: The HDAC inhibitor could reduce the myocardial infarct size and alleviate the myocardial apoptosis induced by MI / R injury. The protective effect of TSA was inhibited after the combined administration of Akt inhibitor. Further studies showed that HDAC inhibitor increased high glucose State myocardial Akt phosphorylation after MI / R injury, but also increased the expression of Akt downstream protein p-Gsk3β. Conclusions: The activation of Akt is a key mechanism of HDAC inhibitor exerting protective effect on diabetes MI / R injury. HDAC inhibitor may play a protective role through Akt / Gsk3β signaling pathway.