p19ARFDeficiency Reduces Macrophage and Vascular Smooth Muscle Cell Apoptosis and Aggravates Atherosclerosis
H González-Navarro, YN Abu Nabah, Á Vinué… - Journal of the American …, 2010 - jacc.org
Journal of the American College of Cardiology, 2010•jacc.org
Objectives: The goal of this study was to investigate the role in atherosclerosis of the tumor
suppressor protein ARF (human p14ARF, mouse p19ARF) 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 …
suppressor protein ARF (human p14ARF, mouse p19ARF) 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 …
Objectives
The goal of this study was to investigate the role in atherosclerosis of the tumor suppressor protein ARF (human p14ARF, mouse p19ARF) encoded by the CDKN2Agene.
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 CDKN2Alocus, the mechanisms underlying this gene–disease association remain undefined, and no causal link has been established between CDKN2Aand atherosclerosis.
Methods
Atherosclerosis-prone apolipoprotein E (apoE)-null and doubly deficient apoE-p19ARFmice 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 p19ARFin apoE-null mice augments aortic atherosclerosis without affecting body weight, plasma lipoproteins, or plaque's proliferative activity. Notably, p19ARFdeficiency 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 p19ARF, plaque apoptosis, and atherosclerosis, and suggest that human genetic variants associated to diminished CDKN2Aexpression may accelerate atherosclerosis by limiting plaque apoptosis.
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