2026-06-30T05:06:40Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/76622024-09-27T08:43:38Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Fuster, Jose J.
author
Molina-Sanchez, Pedro
author
Jovaní, David
author
Vinué, Ángela
author
Serrano, Manuel
author
Andres, Vicente
funder
Ministerio de Ciencia e Innovación (España)
funder
Instituto de Salud Carlos III
funder
Belgian Society of Cardiology
funder
Fundación ProCNIC
2019-05-23T09:38:21Z
2019-05-23T09:38:21Z
2012-03
Atherosclerosis. 2012; 221(1):98-105
10.1016/j.atherosclerosis.2011.12.013
1879-1484
0021-9150
Atherosclerosis
22226369
http://hdl.handle.net/20.500.12105/7662
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.
eng
Increased gene dosage of the Ink4/Arf locus does not attenuate atherosclerosis development in hypercholesterolaemic mice
journal article
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IncreasedGeneDosageInk4Arf_2012.pdf
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IncreasedGeneDosageInk4Arf_2012_suppl.pdf
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IncreasedGeneDosageInk4Arf_2012.pdf.txt
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IncreasedGeneDosageInk4Arf_2012_suppl.pdf.txt