p19ARF Deficiency Reduces Macrophage and Vascular Smooth Muscle Cell Apoptosis and Aggravates Atherosclerosis

Objectives al 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. ound sclerosis 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. s sclerosis-prone apolipoprotein E (apoE)-null and doubly deficient apoE-p19ARF 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. s c disruption of p19ARF in apoE-null mice augments aortic atherosclerosis without affecting body weight, plasma lipoproteins, or plaqueʹs proliferative activity. Notably, p19ARF deficiency significantly attenuates apoptosis both in atherosclerotic lesions and in cultured macrophages and vascular smooth muscle cells, 2 major cellular constituents of atheromatous plaques. sions ndings establish a direct link between p19ARF, plaque apoptosis, and atherosclerosis, and suggest that human genetic variants associated to diminished CDKN2A expression may accelerate atherosclerosis by limiting plaque apoptosis.