Increased gene dosage of the Ink4/Arf locus does not attenuate atherosclerosis development in hypercholesterolaemic mice

被引：11

作者：

Fuster, Jose J. ^{[1
]}

Molina-Sanchez, Pedro ^{[1
]}

Jovani, David ^{[2
]}

Vinue, Angela ^{[2
]}

Serrano, Manuel ^{[3
]}

Andres, Vicente ^{[1
]}

机构：

[1] CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid 28029, Spain

[2] CSIC, IBV, Dept Mol & Cellular Pathol & Therapy, Valencia 46010, Spain

[3] Spanish Natl Canc Res Ctr CNIO, Madrid 28029, Spain

来源：

ATHEROSCLEROSIS | 2012年 / 221卷 / 01期

关键词：

Ink4/Arf; CDKN2A/B; p15(Ink4b); p16(Ink4a); 9p21; Atherosclerosis; CORONARY-ARTERY-DISEASE; DEPENDENT KINASE INHIBITOR; MUSCLE-CELL-PROLIFERATION; RAT CAROTID-ARTERY; CHROMOSOME; 9P21; NEOINTIMA FORMATION; OVER-EXPRESSION; P27(KIP1); ASSOCIATION; MACROPHAGE;

D O I：

10.1016/j.atherosclerosis.2011.12.013

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

引用

页码：98 / 105

页数：8

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