Increased gene dosage of the Ink4/Arf locus does not attenuate atherosclerosis development in hypercholesterolaemic mice
RATIONALE: Human genome-wide association studies have identified genetic variants in the chromosome 9p21 region that confer increased risk of coronary artery disease and other age-related diseases. These variants are located in a block of high linkage disequilibrium with the neighboring Ink4/Arf tum...
| Autores: | , , , , , |
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| Formato: | artículo |
| Fecha de publicación: | 2012 |
| País: | España |
| Recursos: | Instituto de Salud Carlos III (ISCIII) |
| Repositorio: | Repisalud |
| Idioma: | inglés |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/7662 |
| Acesso em linha: | http://hdl.handle.net/20.500.12105/7662 |
| Access Level: | acceso abierto |
| Palavra-chave: | Animals Aorta, Thoracic Aortic Diseases Apolipoproteins E Apoptosis Atherosclerosis Cell Proliferation Cells, Cultured Collagen Cyclin-Dependent Kinase Inhibitor p15 Cyclin-Dependent Kinase Inhibitor p16 Diet, High-Fat Disease Models, Animal Female Hypercholesterolemia Liver Macrophages Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Ultraviolet Rays Gene Dosage |
| Resumo: | RATIONALE: Human genome-wide association studies have identified genetic variants in the chromosome 9p21 region that confer increased risk of coronary artery disease and other age-related diseases. These variants are located in a block of high linkage disequilibrium with the neighboring Ink4/Arf tumor-suppressor locus (also named CDKN2A/CDKN2B). Since previous studies suggest an atheroprotective role of the Ink4/Arf locus, here we assessed whether gain-of-function of the encoded genes can be exploited therapeutically to reduce atherosclerosis. METHODS: Generation and characterization of apolipoprotein E-null mice carrying an additional transgenic copy of the entire Ink4/Arf locus (apoE-/-Super-Ink4/Arf) that reproduces the normal expression and regulation of the endogenous locus. RESULTS: Although liver and aorta of apoE-/-Super-Ink4/Arf mice only showed a trend towards increased Ink4/Arf transcript levels compared to apoE-/- controls, cultured macrophages with increased Ink4/Arf gene dosage exhibited augmented apoptosis induced by irradiation with ultraviolet light, indicating that low level of transgene overexpression can lead to augmented Ink4/Arf function. However, increased Ink4/Arf gene dosage did not affect atherosclerosis development in different vascular regions of both male and female apoE-/- mice fed either normal or high-fat diet. Increased gene dosage of Ink4/Arf similarly had no effect on atheroma cell composition or collagen content, an index of plaque stability. CONCLUSION: In contrast with previous studies demonstrating cancer resistance in Super-Ink4/Arf mice carrying an additional transgenic copy of the entire Ink4/Arf locus, our results cast doubt on the potential of Ink4/Arf activation as a strategy for the treatment of atherosclerotic disease. |
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