dc.contributor.author | Fuster, Jose J. | |
dc.contributor.author | Molina-Sanchez, Pedro | |
dc.contributor.author | Jovaní, David | |
dc.contributor.author | Vinué, Ángela | |
dc.contributor.author | Serrano, Manuel | |
dc.contributor.author | Andres, Vicente | |
dc.date.accessioned | 2019-05-23T09:38:21Z | |
dc.date.available | 2019-05-23T09:38:21Z | |
dc.date.issued | 2012-03 | |
dc.identifier.citation | Atherosclerosis. 2012; 221(1):98-105 | es_ES |
dc.identifier.issn | 0021-9150 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/7662 | |
dc.description.abstract | 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. | es_ES |
dc.description.sponsorship | This work was supported by the Spanish Ministry of Science and Innovation (MICINN) (grant number SAF2010-16044), the Instituto de Salud Carlos III (RECAVA, grant number RD06/0014/0021), and the Dr. Léon Dumont Prize 2010 from the Belgian Society of Cardiology (to V.A.). P.M. is supported by the FPU doctoral fellowship program of the MICINN. The CNIC is supported by the MICINN and the Pro-CNIC Foundation. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.type.hasVersion | AM | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Aorta, Thoracic | es_ES |
dc.subject.mesh | Aortic Diseases | es_ES |
dc.subject.mesh | Apolipoproteins E | es_ES |
dc.subject.mesh | Apoptosis | es_ES |
dc.subject.mesh | Atherosclerosis | es_ES |
dc.subject.mesh | Cell Proliferation | es_ES |
dc.subject.mesh | Cells, Cultured | es_ES |
dc.subject.mesh | Collagen | es_ES |
dc.subject.mesh | Cyclin-Dependent Kinase Inhibitor p15 | es_ES |
dc.subject.mesh | Cyclin-Dependent Kinase Inhibitor p16 | es_ES |
dc.subject.mesh | Diet, High-Fat | es_ES |
dc.subject.mesh | Disease Models, Animal | es_ES |
dc.subject.mesh | Female | es_ES |
dc.subject.mesh | Hypercholesterolemia | es_ES |
dc.subject.mesh | Liver | es_ES |
dc.subject.mesh | Macrophages | es_ES |
dc.subject.mesh | Male | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Mice, Inbred C57BL | es_ES |
dc.subject.mesh | Mice, Knockout | es_ES |
dc.subject.mesh | Mice, Transgenic | es_ES |
dc.subject.mesh | Ultraviolet Rays | es_ES |
dc.subject.mesh | Gene Dosage | es_ES |
dc.title | Increased gene dosage of the Ink4/Arf locus does not attenuate atherosclerosis development in hypercholesterolaemic mice | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 22226369 | es_ES |
dc.format.volume | 221 | es_ES |
dc.format.number | 1 | es_ES |
dc.format.page | 98-105 | es_ES |
dc.identifier.doi | 10.1016/j.atherosclerosis.2011.12.013 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | |
dc.contributor.funder | Instituto de Salud Carlos III | |
dc.contributor.funder | Belgian Society of Cardiology | |
dc.contributor.funder | Fundación ProCNIC | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1879-1484 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1016/j.atherosclerosis.2011.12.013 | es_ES |
dc.identifier.journal | Atherosclerosis | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Fisiopatología Cardiovascular Molecular y Genética | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/SAF2010-16044 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/RD06/0014/0021 | es_ES |
dc.rights.accessRights | open access | es_ES |