12/15-lipoxygenase regulates intercellular adhesion molecule-1 expression and monocyte adhesion to endothelium through activation of RhoA and nuclear factor-κB
12/15-lipoxygenase regulates intercellular adhesion molecule-1 expression and monocyte adhesion to endothelium through activation of RhoA and nuclear factor-κB
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DOI：
10.1161/01.atv.0000186181.19909.a6
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发表时间：
2005-11-01
影响因子：
8.7
通讯作者：
Hedrick, CC
中科院分区：
文献类型：
--
作者：
Bolick, DT;Orr, AW;Hedrick, CC
背景-12/15-脂氧合酶（12/15-LO）活性导致促炎性类二十烷酸12-S-羟基二十碳四烯酸（12 SHETE）和13-S-羟基十八碳二烯酸的产生。我们先前已经显示，在过度表达12/15-LO基因的小鼠中，内皮细胞间粘附分子（ICAM）-1的表达增加了3.5倍。我们研究是否12/15-LO活性调节内皮细胞ICAM-1 expression.Methods和Results-Freshly分离的主动脉内皮细胞（EC）从12/15-LO转基因小鼠有显着更大的核因子-κ B（NF-κ B）的激活和ICAM mRNA的表达相比，C57 BL/6 J控制。12/15-LO转基因EC显示RhoA活性升高，并且使用C3毒素或Rho激酶抑制剂Y-27632抑制RhoA阻断NF-κ B活化、ICAM-1诱导和单核细胞粘附。此外，我们表明，12 SHETE激活蛋白激酶C α，形成一个复合物与活性RhoA和所需的NF-κ B依赖性ICAM的表达在响应12 SHETE.Conclusions-The 12/15-LO途径刺激ICAM-1的表达通过RhoA/蛋白激酶C α依赖性激活NF-κ B。这些发现确定了EC中的一个主要信号通路，12/15-LO通过该通路促进血管炎症和动脉粥样硬化。
Background-12/15-lipoxygenase (12/15-LO) activity leads to the production of the proinflammatory eicosanoids 12-S-hydroxyeicosatetraenoic acid (12SHETE) and 13-S-hydroxyoctadecadienoic acid. We have previously shown a 3.5-fold increase in endothelial intercellular adhesion molecule (ICAM)-1 expression in mice overexpressing the 12/15-LO gene. We examined whether 12/15-LO activity regulated endothelial ICAM-1 expression.Methods and Results-Freshly isolated aortic endothelial cells (EC) from 12/15-LO transgenic mice had significantly greater nuclear factor-kappa B (NF-kappa B) activation and ICAM mRNA expression compared with C57BL/6J control. 12/15-LO transgenic EC showed elevated RhoA activity, and inhibition of RhoA using either C3 toxin or the Rho-kinase inhibitor Y-27632 blocked NF-kappa B activation, ICAM-1 induction, and monocyte adhesion. Furthermore, we show that 12SHETE activates protein kinase C alpha, which forms a complex with active RhoA and is required for NF-kappa B-dependent ICAM expression in response to 12SHETE.Conclusions-The 12/15-LO pathway stimulates ICAM-1 expression through the RhoA/protein kinase C alpha-dependent activation of NF-kappa B. These findings identify a major signaling pathway in EC through which 12/15-LO contributes to vascular inflammation and atherosclerosis.