p66Shc Deletion Confers Vascular Protection in Advanced Atherosclerosis in Hypercholesterolemic Apolipoprotein E Knockout Mice
p66Shc Deletion Confers Vascular Protection in Advanced Atherosclerosis in Hypercholesterolemic Apolipoprotein E Knockout Mice
复制标题
DOI：
10.1080/10623320802487791
复制
发表时间：
2008-01-01
影响因子：
--
通讯作者：
Napoli, Claudio
中科院分区：
文献类型：
--
作者：
Martin-Padura, Ines;de Nigris, Filomena;Napoli, Claudio
先前的研究表明，高脂肪饮食（HFD）的p66Shc -/-小鼠氧化应激、泡沫细胞和早期动脉粥样硬化病变形成减少。在这里，作者使用高胆固醇血症载脂蛋白E （ApoE-/-）小鼠来研究p66Shc缺失在晚期动脉粥样硬化中的作用。作者培育了ApoE和p66Shc基因（ApoE-/- /p66Shc -/-）缺失的小鼠。他们采用微卫星聚合酶链式反应（PCR）分析遗传背景，只考虑具有恒定比例的C57B6L和129SV背景链的动物（C57B6L背景的50.3%为6.4%）。计算机辅助分析显示，ApoE-/-/p66Shc +/+组的晚期动脉粥样硬化病变明显大于ApoE-/-/p66Shc -/-组。因此，ApoE-/-/p66shc +/+ hfd处理组的脂质巨噬细胞泡沫细胞和氧化特异性表位高于正常饮食（ND）处理组。因此，p66Shc -/-对晚期动脉粥样硬化病变的形成也具有重要的保护作用。最后，作者利用微阵列研究了ApoE-/-/p66Shc -/-背景的小鼠，与ApoE-/-/p66Shc +/+相比，经过非常HFD处理的小鼠主动脉中基因表达的主要变化（这些数据已通过实时PCR和免疫组织化学证实）。DAVID （Database for Annotation, Visualization and Integrated Discovery）分析显示，CD36抗原（CD36）、金属蛋白酶2组织抑制剂（TIMP2）、载脂蛋白E （ApoE）、乙酰辅酶A乙酰转移酶1 （ACAT1）和血小板反应蛋白1 （THBS1）可通过脂肪细胞因子/脂质信号通路参与p66缺失依赖性血管保护。
Previous studies showed that p66Shc -/- mice on a very-high-fat diet (HFD) had reduced oxidative stress, foam cell, and early atherosclerotic lesion formation. Here, the authors have used hypercholesterolemic apolipoprotein E (ApoE-/-) mice to investigate the role of p66Shc deletion in advanced atheroma. The authors generated mice deficient of both ApoE and p66Shc genes (ApoE-/- /p66Shc -/-). They used microsatellite polymerase chain reaction (PCR) analysis to analyze the genetic background and considered only animals with a constant percentages of C57B6L and 129SV background strands (it was obtained the 50.3% 6.4% of C57B6L background). Computer-assisted analysis revealed that advanced atherosclerotic lesions in ApoE-/-/p66Shc +/+ were significantly larger than those observed in ApoE-/-/p66Shc -/-. Accordingly, the lipid-laden macrophage foam cells and oxidation-specific epitopes in ApoE-/-/p66shc +/+ HFD-treated groups were higher than those observed in normal diet (ND)-treated groups. Thus, p66Shc -/- plays an important protective role also against advanced atherosclerotic lesion formation. Finally, the authors have used microarray to investigate major changes in gene expression in aortas of mice with ApoE-/-/p66Shc -/- background treated with a very HFD in comparison to ApoE-/-/p66Shc +/+ (these data have been confirmed by by real-time PCR and immunohistochemistry). DAVID (Database for Annotation, Visualization and Integrated Discovery) analysis revealed that CD36 antigen (CD36), tissue inhibitor of metalloproteinase 2 (TIMP2), apolipoprotein E (ApoE), acetyl-coenzyme A acetyltransferase 1 (ACAT1), and thrombospondin 1 (THBS1) can be involved in p66 deletion-dependent vascular protection through the adipocytokine/lipid signaling pathway.