N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats.
N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats.
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DOI：
10.1371/journal.pone.0023967
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Xia Z
中科院分区：
文献类型：
--
作者：
Wang T;Qiao S;Lei S;Liu Y;Ng KF;Xu A;Lam KS;Irwin MG;Xia Z
高血糖引起的氧化应激在糖尿病心肌并发症的发生中起着核心作用。脂联素 (APN) 是一种具有抗糖尿病和抗缺血作用的脂肪因子，在糖尿病中会减少。目前尚不清楚使用 N-乙酰半胱氨酸 (NAC) 和/或别嘌呤醇 (ALP) 进行抗氧化治疗是否可以减轻糖尿病早期 APN 缺乏和心肌缺血再灌注 (MI/R) 损伤。对照或链脲佐菌素 (STZ) 诱导的糖尿病大鼠要么不治疗 (C、D)，要么在注射 STZ 一周后用 NAC（1.5 g/kg/天）或 ALP（100 mg/kg/天）或其组合治疗 4 周。治疗完成后测定血浆和心脏生化参数，并通过闭塞左前降支30分钟然后再灌注2小时对大鼠进行MI/R。糖尿病大鼠血浆和心脏 APN 水平降低，伴有心脏 APN 受体 2 (AdipoR2) 降低，Akt、信号转导和转录激活剂 3 (STAT3) 和内皮一氧化氮合酶 (eNOS) 磷酸化降低，但 IL-6 和 TNF-α 升高（与 C 相比，所有 P<0.05）。 NAC 但 ALP 不会增加糖尿病大鼠的心脏 APN 浓度和 AdipoR2 表达。 ALP 增强 NAC 在恢复糖尿病大鼠心脏 AdipoR2 以及 Akt、STAT3 和 eNOS 磷酸化方面的作用。此外，NAC 和 ALP 分别减少糖尿病大鼠缺血后心肌梗塞的面积和肌酐激酶 MB (CK-MB) 的释放，而它们的组合则具有协同保护作用。此外，将培养的大鼠心肌细胞暴露于高葡萄糖会导致心肌细胞APN浓度和AdipoR2蛋白表达显着降低。 APN 补充可恢复高葡萄糖诱导的心肌细胞中 AdipoR2 的减少。 NAC 和 ALP 协同恢复心肌 APN 和 AdipoR2 介导的 eNOS 激活。这可能代表了 NAC 和 ALP 组合大大减轻早期糖尿病大鼠 MI/R 损伤的机制。
Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes. Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes. NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated eNOS activation. This may represent the mechanism through which NAC and ALP combination greatly reduces MI/R injury in early diabetic rats.