p66Shc deletion confers vascular protection in advanced atherosclerosis in hypercholesterolemic apolipoprotein E knockout mice.

Ines Martin-Padura, Filomena de Nigris, Enrica Migliaccio, Gelsomina Mansueto, Simone Minardi, Monica Rienzo, Lilach O Lerman, Massimo Stendardo, Marco Giorgio, Gaetano De Rosa, Pier Giuseppe Pelicci, Claudio Napoli
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引用次数: 50

Abstract

Previous studies showed that p66(Shc-/-) 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(-/-) /p66(Shc-/-)). 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(-/-)/p66(Shc+/+) were significantly larger than those observed in ApoE(-/-)/p66(Shc-/-). Accordingly, the lipid-laden macrophage foam cells and oxidation-specific epitopes in ApoE(-/-)/p66(shc+/+) HFD-treated groups were higher than those observed in normal diet (ND)-treated groups. Thus, p66(Shc-/-) 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(-/-)/p66(Shc-/-) background treated with a very HFD in comparison to ApoE(-/-)/p66(Shc+/+) (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.

p66Shc缺失在高胆固醇血症载脂蛋白E敲除小鼠晚期动脉粥样硬化中赋予血管保护作用。
先前的研究表明,高脂肪饮食(HFD)的p66(Shc-/-)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(-/-) /p66(Shc-/-))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(得到50.3% +/- 6.4%的C57B6L背景)。计算机辅助分析显示,ApoE(-/-)/p66(Shc+/+)的晚期动脉粥样硬化病变明显大于ApoE(-/-)/p66(Shc-/-)。因此,ApoE(-/-)/p66(shc+/+) 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,p66(Shc-/-)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(-/-)/p66(Shc-/-)背景小鼠与ApoE(-/-)/p66(Shc+/+)背景小鼠主动脉中基因表达的主要变化(这些数据已通过实时荧光定量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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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