12/15 lipoxygenase mediates monocyte adhesion to aortic endothelium in apolipoprotein E-deficient mice through activation of RhoA and NF-κB
12/15 lipoxygenase mediates monocyte adhesion to aortic endothelium in apolipoprotein E-deficient mice through activation of RhoA and NF-κB
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DOI：
10.1161/01.atv.0000217909.09198.d6
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发表时间：
2006-06-01
影响因子：
8.7
通讯作者：
Hedrick, Catherine C.
中科院分区：
文献类型：
--
作者：
Bolick, David T.;Srinivasan, Suseela;Hedrick, Catherine C.
目的：12/15脂氧合酶（12/15 LO）是炎症和动脉粥样硬化的介质。在目前的研究中，我们确定了机制，通过12/15 LO介导单核细胞：内皮细胞的相互作用在体内载脂蛋白E缺陷小鼠（apoEKO），一个良好的特点的小鼠模型动脉粥样硬化。方法和结果-在apoEKO小鼠，也缺乏12/15 LO（doubleKO），单核细胞粘附到主动脉在体内减少了95%，在doubleKO小鼠相比，apoEKO小鼠。使用CDC（肉桂基-3，4-二羟基-α-氰基肉桂酸酯）在体内抑制apoEKO小鼠中的12/15 LO防止apoEKO小鼠中单核细胞粘附到主动脉内皮。apoEKO小鼠的主动脉内皮与doubleKO主动脉内皮相比具有显著的rhoA活化。此外，apoEKO主动脉显示NF-κ B的显著活化。DoubleKO主动脉显示NF-κ B的核定位很少。最后，我们发现apoEKO主动脉内皮细胞间粘附分子-1（ICAM-1）的表达显著上调。rhoA和PKC α的抑制显着减少NF-κ B B激活，ICAM-1诱导，单核细胞粘附到aorator.Conclusions -我们得出结论，12/15 LO产品激活内皮rhoA和PKC α。rhoA和PKC α的激活引起NF-κ B的激活和易位到细胞核，这反过来又导致ICAM-1的诱导。在apoEKO小鼠中，主动脉内皮上ICAM- 1的诱导刺激体内单核细胞：内皮粘附。
Objectives - 12/15 lipoxygenase ( 12/15LO) has been implicated as a mediator of inflammation and atherosclerosis. In the current study, we identified mechanisms through which 12/15LO mediates monocyte: endothelial interactions in vivo in apolipoprotein E-deficient mice ( apoEKO), a well-characterized mouse model of atherosclerosis.Methods and Results - In apoEKO mice that are also deficient in 12/15LO ( doubleKO), monocyte adhesion to aorta in vivo was reduced by 95% in doubleKO mice compared with apoEKO mice. Inhibition of 12/15LO in apoEKO mice in vivo using CDC ( Cinnamyl-3,4-Dihydroxy-a-Cyanocinnamate) prevented monocyte adhesion to aortic endothelium in apoEKO mice. Aortic endothelium of apoEKO mice had significant activation of rhoA compared with doubleKO aortic endothelium. Further, apoEKO aorta displayed significant activation of NF-kappa B. DoubleKO aorta displayed little nuclear localization of NF-kappa B. Finally, we found significant upregulation of intercellular adhesion molecule-1 ( ICAM-1) on apoEKO aortic endothelium compared with doubleKO endothelium. Inhibition of rhoA and PKC alpha significantly reduced NF-kappa B activation, ICAM-1 induction, and monocyte adhesion to aorta.Conclusions - We conclude that 12/15LO products activate endothelial rhoA and PKC alpha. Activation of rhoA and PKC alpha cause activation and translocation of NF-kappa B to the nucleus, which, in turn, results in induction of ICAM-1. Induction of ICAM- 1 on aortic endothelium stimulates monocyte: endothelial adhesion in vivo in apoEKO mice.