title: p66Shc deletion confers vascular protection in advanced atherosclerosis in hypercholesterolemic apolipoprotein E knockout mice.
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.
authors.affiliation: European Institute of Oncology (EIO), Milan, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Martin-Padura
authors.forename: Filomena
authors.initials: F
authors.lastname: de Nigris
authors.forename: Enrica
authors.initials: E
authors.lastname: Migliaccio
authors.forename: Gelsomina
authors.initials: G
authors.lastname: Mansueto
authors.forename: Simone
authors.initials: S
authors.lastname: Minardi
authors.forename: Monica
authors.initials: M
authors.lastname: Rienzo
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.forename: Massimo
authors.initials: M
authors.lastname: Stendardo
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.forename: Gaetano
authors.initials: G
authors.lastname: De Rosa
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Claudio
authors.initials: C
authors.lastname: Napoli
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D005526:Food, Formulated / Q000009:adverse effects; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D054392:Adipokines; D001057:Apolipoproteins E; D004041:Dietary Fats; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1