Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells
Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells
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DOI：
10.1152/ajpheart.00431.2009
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发表时间：
2010-07-01
影响因子：
4.8
通讯作者：
Yao, Qizhi
中科院分区：
文献类型：
--
作者：
Chen, Changyi;Jiang, Jun;Yao, Qizhi
Chen C，Jiang J，Lu J，Chai H，Wang X，Lin PH，Yao Q。抵抗素通过人冠状动脉内皮细胞的氧化应激降低内皮一氧化氮合酶的表达。 Am J Physiol Heart Circ Physiol 299：H193-H201，2010。首次发表于 2010 年 4 月 30 日； doi:10.1152/ajpheart.00431.2009.-抵抗素是一种新发现的脂肪细胞衍生的细胞因子，可能在胰岛素抵抗、糖尿病、脂肪生成、炎症和心血管疾病中发挥重要作用。然而，抵抗素是否通过影响内皮一氧化氮合酶（eNOS）系统来损害内皮功能尚不清楚。在本研究中，我们确定了人重组抵抗素蛋白对人冠状动脉内皮细胞 (HCAEC) 中 eNOS 表达和调节的影响。当细胞用临床相关浓度的抵抗素（40 或 80 ng/ml）处理 24 小时时，eNOS mRNA、蛋白质和活性的水平以及 eNOS mRNA 稳定性显着降低。细胞一氧化氮水平也降低。此外，在抵抗素处理的 HCAEC 中，包括超氧阴离子在内的活性氧 (ROS) 的细胞水平显着增加。线粒体膜电位以及过氧化氢酶和超氧化物歧化酶的活性降低。硒代 L-蛋氨酸、人参皂苷 Rb1 和 MnTBAP（超氧化物歧化酶模拟物）这三种抗氧化剂可有效阻止抵抗素诱导的 eNOS 下调。同时，抵抗素激活丝裂原激活蛋白激酶p38和c-Jun NH(2)末端激酶(JNK)，特异性p38抑制剂SB-239063有效阻断抵抗素诱导的ROS产生和eNOS下调。此外，在人主动脉和颈动脉的动脉粥样硬化区域，抵抗素的免疫反应性增加。因此，抵抗素通过 HCAEC 中 ROS 的过量产生以及 p38 和 JNK 的激活直接诱导 eNOS 下调。抵抗素诱导的线粒体功能障碍和细胞氧化还原酶失衡可能是氧化应激的潜在机制。
Chen C, Jiang J, Lu J, Chai H, Wang X, Lin PH, Yao Q. Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Am J Physiol Heart Circ Physiol 299: H193-H201, 2010. First published April 30, 2010; doi:10.1152/ajpheart.00431.2009.-Resistin is a newly discovered adipocyte-derived cytokine that may play an important role in insulin resistance, diabetes, adipogenesis, inflammation, and cardiovascular disease. However, it is largely unknown whether resistin impairs endothelial functions by affecting the endothelial nitric oxide synthase (eNOS) system. In this study, we determined the effect of human recombinant resistin protein on eNOS expression and regulation in human coronary artery endothelial cells (HCAECs). When cells were treated with clinically relevant concentrations of resistin (40 or 80 ng/ml) for 24 h, the levels of eNOS mRNA, protein, and activity and eNOS mRNA stability were significantly reduced. Cellular nitric oxide levels were also decreased. In addition, the cellular levels of reactive oxygen species (ROS), including superoxide anion, were significantly increased in resistin-treated HCAECs. Mitochondrial membrane potential and the activities of catalase and superoxide dismutase were reduced. Three antioxidants, seleno-L-methionine, ginsenoside Rb1, and MnTBAP (superoxide dismutase mimetic), effectively blocked resistin-induced eNOS downregulation. Meanwhile, resistin activated the mitogen-activated protein kinases p38 and c-Jun NH(2)-terminal kinase (JNK), and the specific p38 inhibitor SB-239063 effectively blocked resistin-induced ROS production and eNOS downregulation. Furthermore, immunoreactivity of resistin was increased in atherosclerotic regions of human aorta and carotid arteries. Thus resistin directly induces eNOS downregulation through overproduction of ROS and activation of p38 and JNK in HCAECs. Resistin-induced mitochondrial dysfunction and imbalance in cellular redox enzymes may be the underlying mechanisms of oxidative stress.