p19(ARF) deficiency reduces macrophage and vascular smooth muscle cell apoptosis and aggravates atherosclerosis.
OBJECTIVE
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.
González-Navarro
Herminia
H
Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia , Spanish Council for Scientific Research, Valencia, Spain.
Abu Nabah
Yafa Naim
YN
Vinué
Angela
A
Andrés-Manzano
María J
MJ
Collado
Manuel
M
Serrano
Manuel
M
Andrés
Vicente
V
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics*; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D019942:Genes, p16 / Q000502:physiology*; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16