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

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

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43 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)276-287
Number of pages12
JournalEndothelium: Journal of Endothelial Cell Research
Issue number5-6
StatePublished - 2008


  • ApoE
  • Atherosclerosis
  • p66Shc

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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