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Published on: May 17, 2015
p19(ARF) deficiency reduces macrophage and vascular smooth muscle cell apoptosis and aggravates atherosclerosis
Herminia González-Navarro1, Yafa Naim Abu Nabah, Angela Vinué
1Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia , Spanish Council for Scientific Research, Valencia, Spain.
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.
Insights
The tumor suppressor protein ARF (p19(ARF)) limits plaque apoptosis, directly linking it to atherosclerosis. Diminished CDKN2A expression may accelerate atherosclerosis by reducing this protective apoptosis.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Tumor Suppressor Mechanisms
Background:
- Atherosclerosis involves dysregulated proliferation and apoptosis, cellular processes influenced by the CDKN2A gene.
- Genome-wide association studies suggest a link between the 9p21 locus, near CDKN2A, and atherosclerotic diseases, but the underlying mechanisms are unclear.
- A direct causal relationship between CDKN2A and atherosclerosis has not been established.
Discussion:
- Genetic deletion of p19(ARF) in apolipoprotein E-null mice exacerbates aortic atherosclerosis.
- p19(ARF) deficiency markedly reduces apoptosis in atherosclerotic lesions and in macrophages and vascular smooth muscle cells.
- These findings highlight the critical role of p19(ARF) in regulating cellular apoptosis within atherosclerotic plaques.
Key Insights:
- p19(ARF) deficiency augments atherosclerosis in apoE-null mice without altering body weight or lipoproteins.
- p19(ARF) deficiency significantly attenuates apoptosis in atherosclerotic lesions and key cellular components.
- A direct link is established between p19(ARF), plaque apoptosis, and the development of atherosclerosis.
Outlook:
- Human genetic variants associated with reduced CDKN2A expression may accelerate atherosclerosis.
- Targeting p19(ARF) or pathways regulating plaque apoptosis could offer novel therapeutic strategies for atherosclerosis.
- Further research is warranted to elucidate the precise molecular mechanisms by which p19(ARF) influences atherogenesis.
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