Diabetes aggravates myocardial ischaemia reperfusion injury via activating Nox2-related programmed cell death in an AMPK-dependent manner
Diabetes aggravates myocardial ischaemia reperfusion injury via activating Nox2-related programmed cell death in an AMPK-dependent manner
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糖尿病通过AMPK依赖性激活Nox2相关程序性细胞死亡加重心肌缺血再灌注损伤
DOI：
10.1111/jcmm.15318
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发表时间：
2020-06-01
影响因子：
5.3
通讯作者：
Yao, Weifeng
中科院分区：
文献类型：
--
作者：
Wang, Chunyan;Zhu, Lijie;Yao, Weifeng
心血管疾病如心肌缺血在糖尿病患者中有很高的病死率。本研究旨在揭示糖尿病大鼠心肌缺血再灌注损伤（I/RI）中氧化应激与AMPK（一种控制生物能量代谢的重要分子）之间的串扰。糖尿病大鼠用链脲佐菌素注射刺激。将大鼠随机分为对照组、对照+ I/R组、糖尿病组、糖尿病+ I/R组、糖尿病+ I/R + N-乙酰半胱氨酸组和糖尿病+ I/R + Vas 2870组。测定心肌梗死面积，并分析主要的Nox家族亚型。在体外，H9 C2细胞被给予过量的葡萄糖并暴露于缺氧/复氧以模拟糖尿病和I/R。AMPK siRNA或AICAR分别用于抑制或激活H9 C2细胞中AMPK的表达。测定心肌氧化应激和程序性细胞死亡。糖尿病或高葡萄糖水平被发现加剧心肌I/RI或缺氧/复氧在H9 C2细胞，心肌梗死面积或乳酸脱氢酶水平的增加，氧化应激的产生和诱导程序性细胞死亡证明。在糖尿病大鼠心脏中，心脏Nox 1、Nox 2和Nox 4均升高。分别在体内或体外使用Vas 2870或Nox 2-siRNA治疗抑制Nox 2表达，保护糖尿病大鼠免受心肌I/RI。AMPK基因敲除增加Nox 2蛋白表达，而AMPK激动剂降低Nox 2蛋白表达。因此，糖尿病通过AMPK依赖性的方式产生Nox 2相关的氧化应激，从而诱导程序性细胞死亡，如细胞凋亡、焦亡和铁亡，从而加重心肌I/RI。
Cardiovascular diseases such as myocardial ischaemia have a high fatality rate in patients with diabetes. This study was designed to expose the crosstalk between oxidative stress and AMPK, a vital molecule that controls biological energy metabolism, in myocardial ischaemia reperfusion injury (I/RI) in diabetic rats. Diabetes was stimulated in rats using streptozotocin injection. Rats were separated on random into control, control + I/R, Diabetes, Diabetes + I/R, Diabetes + I/R + N-acetylcysteine and Diabetes + I/R + Vas2870 groups. Myocardial infarct size was determined, and the predominant Nox family isoforms were analysed. In vitro, the H9C2 cells were administered excess glucose and exposed to hypoxia/reoxygenation to mimic diabetes and I/R. The AMPK siRNA or AICAR was used to inhibit or activate AMPK expression in H9C2 cells, respectively. Then, myocardial oxidative stress and programmed cell death were measured. Diabetes or high glucose levels were found to aggravate myocardial I/RI or hypoxia/reoxygenation in H9C2 cells, as demonstrated by an increase in myocardial infarct size or lactate dehydrogenase levels, oxidative stress generation and induction of programmed cell death. In diabetic rat hearts, cardiac Nox1, Nox2 and Nox4 were all heightened. The suppression of Nox2 expression using Vas2870 or Nox2-siRNA treatment in vivo or in vitro,respectively, protected diabetic rats from myocardial I/RI. AMPK gene knockout increased Nox2 protein expression while AMPK agonist decreased Nox2 expression. Therefore, diabetes aggravates myocardial I/RI by generating of Nox2-associated oxidative stress in an AMPK-dependent manner, which led to the induction of programmed cell death such as apoptosis, pyroptosis and ferroptosis.