TY - JOUR
T1 - p66Shc deletion confers vascular protection in advanced atherosclerosi in hypercholesterolemic apolipoprotein E knockout mice
AU - Martin-Padura, Ines
AU - de Nigris, Filomena
AU - Migliaccio, Enrica
AU - Mansueto, Gelsomina
AU - Minardi, Simone
AU - Rienzo, Monica
AU - Lerman, Lilach
AU - Stendardo, Massimo
AU - Giorgio, Marco
AU - De Rosa, Gaetano
AU - Pelicci, Pier Giuseppe
AU - Napoli, Claudio
N1 - Funding Information:
Ines Martin-Padura and Filomena de Nigris contributed equally to this work. This study was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro), by ISS (Istituto Superiore di Sanità), the sixth EU Framework Programme (Integrated Project “Angiotargeting” contract n◦504743) in the area of “Life Sciences, Genomics and Biotechnology for Health” to Prof. Pelicci, Mayo Foundation grants (Dr. Lerman), and PRIN-MIUR 2006 to Prof. Napoli. Address correspondence to Professor Claudio Napoli, MD, PhD, Department of General Pathology, Division of Clinical Pathology, and Excellence Research Center on Cardiovascular Diseases, School of Medicine, IInd University of Naples, via De Crecchio, 7, 80138 Naples, Italy. E-mail: claudio.napoli@unina2.it. Tel: +39 081 5667567; Fax: 081 450169.
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - ApoE
KW - Atherosclerosis
KW - p66Shc
UR - http://www.scopus.com/inward/record.url?scp=60549112093&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=60549112093&partnerID=8YFLogxK
U2 - 10.1080/10623320802487791
DO - 10.1080/10623320802487791
M3 - Article
C2 - 19065319
AN - SCOPUS:60549112093
SN - 1062-3329
VL - 15
SP - 276
EP - 287
JO - Endothelium: Journal of Endothelial Cell Research
JF - Endothelium: Journal of Endothelial Cell Research
IS - 5-6
ER -