Generation of plasma oxidized LDL in the early stages of atherogenesis

10周龄apoE基因敲除小鼠主动脉内膜和内侧可见脂质过氧化产物沉积，形成的动脉粥样硬化病变很少。对易形成动脉粥样硬化病变的两种主动脉组织，即主动脉起源和主动脉弓，以及较晚形成动脉粥样硬化病变的胸、腹主动脉的蛋白质谱进行了检测。我们发现，在动脉粥样硬化易感组织中，抗氧化应激酶2(Prx2)和平滑肌细胞分化标志物SM22的表达减少，提示动脉粥样硬化易感组织可能降低了其抗氧化应激潜能，增加了平滑肌分化状态。在主动脉起源处，Prx2在4周龄时高表达，在10周龄和20周龄时低表达。在Prx2高表达的中层部位，几乎没有观察到巨噬细胞向邻近内膜迁移。当内膜内有少量巨噬细胞时，邻近的中层组织Prx2的表达很低。巨噬细胞向内膜的迁移可能是通过减少中膜Prx2的表达来实现的。在内膜增厚并有大量巨噬细胞聚集的病变中，Prx2在中膜和内膜组织中的表达均增加。炎症细胞在内膜中的积聚可促进中膜Prx2的表达。根据这些观察，在小鼠动脉粥样硬化形成的非常早期阶段，抗氧化酶Prx2表达的减少可能会增加组织中的氧化应激，并诱导脂质过氧化。这样的时间变化将是触发动脉粥样硬化早期步骤的重要事件。

Deposition of lipid peroxidation products was found in intimal and medial regions in aortas of apoE-knockout mice at 10 week old in which very little atherosclerotic lesion was formed. The protein profiles of the two aortic tissues, aortic origin and aortic arch which are prone to atherosclerotic lesion formation, and thoracic and abdominal aortas which form atherosclerotic lesions much later, were examined. We found that peroxiredoxin 2(Prx2), an anti-oxidative stress enzyme, and SM22, a marker for smooth muscle cell differentiation, were reduced expressions in the athero-prone tissues, suggesting a possibility that athero-prone tissue reduces its anti-oxidative stress potential and increase smooth muscle differentiation status. In aortic origin, Prx2 expression was high at 4 weeks of age and lower at 10 and 20 weeks of age. At sites of medial layer with high expression of Prx2, migration of macrophages into adjacent intima was scarcely observed. When a few macrophages are present in intima, the adjacent medial tissue has very low expression of Prx2. It is possible that transmigration of macrophages into intima may be facilitated by reduction of medial Prx2 expression. In the lesions with intimal thickening with a number of accumulated macrophages Prx2 expression increased in both medial and intimal tissues. Accumulation of inflammatory cells in intima could enhance Prx2 expression in media. From these observations, in the very early stages of atherogenesis in mouse aortas, decrease in anti-oxidative enzyme Prx2 expression could increase oxidative stress in the tissues and induce lipid peroxidation. Such a temporal change would be important event as a trigger of the early steps of atherogenesis.