期刊
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 55, 期 20, 页码 2258-2268出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2010.01.026
关键词
ARF; CDKN2A; atherosclerosis; apoptosis; macrophage; vascular smooth muscle cell
资金
- Spanish Ministry of Science and Innovation (MICINN)
- European Regional Development Fund [SAF2007-62110]
- Instituto de Salud Carlos III (ISCIII) [RD06/0014/0021]
- Pro-CNIC Foundation
Objectives The goal of this study was to investigate the role in atherosclerosis of the tumor suppressor protein ARF (human p14(ARF), mouse p19(ARF)) encoded by the CDKN2A gene. Background Atherosclerosis is characterized by excessive proliferation and apoptosis, 2 cellular processes regulated by CDKN2A. Although recent genome-wide association studies have linked atherosclerotic diseases to a genomic region in human chromosome 9p21 near the CDKN2A locus, the mechanisms underlying this gene-disease association remain undefined, and no causal link has been established between CDKN2A and atherosclerosis. Methods Atherosclerosis-prone apolipoprotein E (apoE)-null and doubly deficient apoE-p19(ARF) mice were fed an atherogenic diet and sacrificed to quantify atherosclerosis burden in whole-mounted aortas and in aortic cross-sections. Proliferation and apoptosis were investigated in atherosclerotic lesions and in primary cultures of macrophages and vascular smooth muscle cells obtained from both groups of mice. Results Genetic disruption of p19(ARF) in apoE-null mice augments aortic atherosclerosis without affecting body weight, plasma lipoproteins, or plaque's proliferative activity. Notably, p19(ARF) deficiency significantly attenuates apoptosis both in atherosclerotic lesions and in cultured macrophages and vascular smooth muscle cells, 2 major cellular constituents of atheromatous plaques. Conclusions Our findings establish a direct link between p19(ARF), plaque apoptosis, and atherosclerosis, and suggest that human genetic variants associated to diminished CDKN2A expression may accelerate atherosclerosis by limiting plaque apoptosis. (J Am Coll Cardiol 2010;55:2258-68) (C) 2010 by the American College of Cardiology Foundation
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