Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes
Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes
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DOI：
10.1016/j.yjmcc.2008.10.007
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发表时间：
2009-01-01
影响因子：
5
通讯作者：
Ma, Qiang
中科院分区：
文献类型：
--
作者：
He, Xiaoqing;Kan, Hong;Ma, Qiang
暴露于高水平的葡萄糖诱导心肌细胞产生活性氧（ROS），这可能有助于糖尿病心肌病的发展。核因子红系2相关因子2 （Nrf2）控制氧化应激反应中抗氧化反应元件（ARE）依赖基因的调控。研究了Nrf2在心肌细胞防御高糖诱导的氧化损伤中的作用。高浓度葡萄糖诱导来自Nrf2野生型（WT）小鼠心脏的初生和成年心肌细胞产生ROS，而在Nrf2敲除（KO）细胞中，ROS在基础条件下显著升高，高葡萄糖以浓度和时间依赖性的方式显著进一步增加ROS的产生。同时，在较低浓度和较短时间内，高糖诱导Nrf2 KO细胞的凋亡水平显著高于WT细胞。来自对照组和糖尿病小鼠的原代成年心肌细胞也显示出对Nrf2功能的依赖，以促进异丙肾上腺素刺激的收缩。此外，与Nrf2 WT细胞相比，Nrf2 KO小鼠心肌细胞对线粒体呼吸复合物11抑制剂3-硝基丙酸对ROS产生和凋亡的敏感性增加，进一步强调了Nrf2在细胞中ROS防御中的作用。从机制上讲，Nrf2在心肌细胞mRNA和蛋白水平上介导了re -controlled细胞保护基因Nqo1和Ho1的基础表达和诱导，因为Nrf2 KO细胞中这些基因的基础表达和诱导表达都缺失或被Nrf2 SiRNA大量降低。这一发现首次证实了Nrf2在正常心脏和糖尿病心脏中是防御活性氧的关键调节因子。Elsevier Inc.出版。
Exposure to high levels of glucose induces the production of reactive oxygen species (ROS) in cardiomyocytes that may contribute to the development of cardiomyopathy in diabetes. Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the antioxidant response element (ARE)-dependent gene regulation in response to oxidative stress. The role of Nrf2 in defense against high glucose-induced oxidative damage in cardiomyocytes was investigated. Glucose at high concentrations induced ROS production in both primary neonatal and adult cardiomyocytes from the Nrf2 wild type (WT) mouse heart, whereas, in Nrf2 knockout (KO) cells, ROS was significantly higher under basal conditions and high glucose markedly further increased ROS production in concentration and time-dependent manners. Concomitantly, high glucose induced significantly higher levels of apoptosis at lower concentrations and in shorter time in Nrf2 KO cells than in WT cells. Primary adult cardiomyocytes from control and diabetic mice also showed dependence on Nrf2 function for isoproterenol-stimulated contraction. Additionally, cardiomyocytes from Nrf2 KO mice exhibited increased sensitivity to 3-nitropropionic acid, an inhibitor of mitochondrial respiratory complex 11, for both ROS production and apoptosis compared with Nrf2 WT cells, further emphasizing the role of Nrf2 in ROS defense in the cells. Mechanistically, Nrf2 was shown to mediate the basal expression and induction of ARE-controlled cytoprotective genes, Nqo1 and Ho1, at both mRNA and protein levels in cardiomyocytes, as both the basal and inducible expressions of the genes were lost in Nrf2 KO cells or largely reduced by Nrf2 SiRNA. The findings, for the first time, established Nrf2 as a critical regulator of defense against ROS in normal and diabetic hearts. Published by Elsevier Inc.