Soluble CD40 ligand induces endothelial dysfunction in human and porcine coronary artery endothelial cells
Soluble CD40 ligand induces endothelial dysfunction in human and porcine coronary artery endothelial cells
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DOI：
10.1182/blood-2008-03-143479
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发表时间：
2008-10-15
期刊：
影响因子：
20.3
通讯作者：
Yao, Qizhi
中科院分区：
文献类型：
--
作者：
Chen, Changyi;Chai, Hong;Yao, Qizhi
本研究旨在探讨sCD 40 L对人冠状动脉内皮细胞（HCAECs）和猪冠状动脉环内皮功能障碍的影响及其机制。sCD 40 L处理的HCAEC显示内皮型一氧化氮合酶（eNOS）mRNA和蛋白水平、eNOS mRNA稳定性、eNOS酶活性和细胞NO水平显著降低，而超氧阴离子（O-2（-））产生显著增加。sCD 40 L增强eNOS mRNA 3 'UTR与胞质分子的结合，并诱导95种microRNA的独特表达模式。sCD 40 L可显著降低线粒体膜电位、过氧化氢酶和SOD活性，提高NADPH氧化酶（NOX）活性。sCD 40 L增加MAPK p38和ERK 1/2以及I κ B α的磷酸化，并增强NF-κ B核转位。在猪冠状动脉，sCD 40 L显着降低内皮依赖性血管舒张和eNOS mRNA水平，而它增加O-2-水平。抗氧化剂硒-L-蛋氨酸; p38、ERK 1/2和线粒体复合物II的化学抑制剂以及I κ B α和NOX 4的显性负突变形式有效地阻断了HCAEC中sCD 40 L诱导的eNOS下调。因此，sCD 40 L降低eNOS水平，而通过独特的分子机制增加氧化应激，该机制涉及内皮细胞中eNOS mRNA稳定性、3 'UTR结合分子、microRNA、线粒体功能、ROS相关酶、p38、ERK 1/2和NF-κ B信号通路。
The purpose of this study was to determine the effects and mechanisms of sCD40L on endothelial dysfunction in both human coronary artery endothelial cells (HCAECs) and porcine coronary artery rings. HCAECs treated with sCD40L showed significant reductions of endothelial nitric oxide synthase (eNOS) mRNA and protein levels, eNOS mRNA stability, eNOS enzyme activity, and cellular NO levels, whereas superoxide anion (O-2(-)) production was significantly increased. sCD40L enhanced eNOS mRNA 3'UTR binding to cytoplasmic molecules and induced a unique expression pattern of 95 microRNAs. sCD40L significantly decreased mitochondrial membrane potential, and catalase and SOD activities, whereas it increased NADPH oxidase (NOX) activity. sCD40L increased phosphorylation of MAPKs p38 and ERK1/2 as well as I kappa B alpha and enhanced NF-kappa B nuclear translocation. In porcine coronary arteries, sCD40L significantly decreased endothelium-dependent vasorelaxation and eNOS mRNA levels, whereas it increased O-2-levels. Antioxidant seleno-L-methionine; chemical inhibitors of p38, ERK1/2, and mitochondrial complex II; as well as dominant negative mutant forms of I kappa B alpha and NOX4 effectively blocked sCD40L-induced eNOS down-regulation in HCAECs. Thus, sCD40L reduces eNOS levels, whereas it increases oxidative stress through the unique molecular mechanisms involving eNOS mRNA stability, 3'UTR-binding molecules, microRNAs, mitochondrial function, ROS-related enzymes, p38, ERK1/2, and NF-kappa B signal pathways in endothelial cells.