ABSTRACT
Abdominal aortic aneurysm (AAA) is a common chronic degenerative disease characterized by progressive aortic dilation and rupture. The mechanisms underlying the role of α-tocopherol and ß-carotene on AAA have not been comprehensively assessed. We investigated if α-tocopherol and ß-carotene supplementation could attenuate AAA, and studied the underlying mechanisms utilized by the antioxidants to alleviate AAA. Four-months-old Apoe(-/-) mice were used in the induction of aneurysm by infusion of angiotensin II (Ang II), and were orally administered with α-tocopherol and ß-carotene enriched diet for 60 days. Significant increase of LDL, cholesterol, triglycerides and circulating inflammatory cells was observed in the Ang II-treated animals, and gene expression studies showed that ICAM-1, VCAM-1, MCP-1, M-CSF, MMP-2, MMP-9 and MMP-12 were upregulated in the aorta of aneurysm-induced mice. Extensive plaques, aneurysm and diffusion of inflammatory cells into the tunica intima were also noticed. The size of aorta was significantly (Pâ=â0.0002) increased (2.24±0.20 mm) in the aneurysm-induced animals as compared to control mice (1.17±0.06 mm). Interestingly, ß-carotene dramatically controlled the diffusion of macrophages into the aortic tunica intima, and circulation. It also dissolved the formation of atheromatous plaque. Further, ß-carotene significantly decreased the aortic diameter (1.33±0.12 mm) in the aneurysm-induced mice (ß-carotene, Pâ=â0.0002). It also downregulated ICAM-1, VCAM-1, MCP-1, M-CSF, MMP-2, MMP-9, MMP-12, PPAR-α and PPAR-γ following treatment. Hence, dietary supplementation of ß-carotene may have a protective function against Ang II-induced AAA by ameliorating macrophage recruitment in Apoe(-/-) mice.
Subject(s)
Aortic Aneurysm, Abdominal/diet therapy , Apolipoproteins E/deficiency , Dietary Supplements , Macrophages/metabolism , alpha-Tocopherol/administration & dosage , beta Carotene/administration & dosage , Angiotensin II , Animals , Antioxidants/administration & dosage , Aorta, Abdominal/immunology , Aorta, Abdominal/pathology , Aortic Aneurysm, Abdominal/immunology , Aortic Aneurysm, Abdominal/pathology , Apolipoproteins E/genetics , Cholesterol, LDL/metabolism , Disease Models, Animal , Lymphocytes/metabolism , Lymphocytes/pathology , Macrophages/pathology , Male , Mice, Knockout , Organ Size , Plaque, Atherosclerotic/diet therapy , Plaque, Atherosclerotic/immunology , Plaque, Atherosclerotic/pathologyABSTRACT
BACKGROUND: Anchorage independent growth is an important hallmark of oncogenic transformation. Previous studies have shown that when adhesion dependent fibroblasts were prevented from adhering to a substrate they underwent anoikis. In the present study we have demonstrated how anoikis resistant cells gain the transformation related properties with sequential selection of genes. We have proposed this process as a model system for selection of transformed cells from normal cells. RESULTS: This report demonstrates that some fibroblasts can survive during late stages of anoikis, at which time they exhibit transformation-associated properties such as in vitro colony formation in soft agar and in vivo subcutaneous tumour formation in nude mice. Cytogenetic characterisation of these cells revealed that they contained a t (2; 2) derivative chromosome and they have a selective survival advantage in non adherent conditions. Gene expression profile indicated that these cells over expressed genes related to hypoxia, glycolysis and tumor suppression/metastasis which could be helpful in their retaining a transformed phenotype. CONCLUSION: Our results reveal some new links between anoikis and cell transformation and they provide a reproducible model system which can potentially be useful to study multistage cancer and to identify new targets for drug development.
