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PRE-CLINICAL RESEARCH

p19^ARF Deficiency Reduces Macrophage and Vascular Smooth Muscle Cell Apoptosis and Aggravates Atherosclerosis

Herminia González-Navarro, PhD^_*, Yafa Naim Abu Nabah, PhD^_*, Ángela Vinué, BSc^_*, María J. Andrés-Manzano, BSc, Manuel Collado, PhD, Manuel Serrano, PhD and Vicente Andrés, PhD^_*,,_*

^_* Vascular Biology Unit, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia (IBV), Spanish Council for Scientific Research (CSIC), Valencia, Spain
Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Department of Atherothrombosis and Cardiovascular Imaging, Spanish National Cardiovascular Research Center (CNIC), Madrid, Spain
Spanish National Cancer Research Center (CNIO), Madrid, Spain

Manuscript received December 4, 2009; revised manuscript received January 14, 2010, accepted January 18, 2010.

^_* Reprint requests and correspondence: Dr. Vicente Andrés, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain (Email: vandres{at}cnic.es).

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.

Key Words: ARF • CDKN2A • atherosclerosis • apoptosis • macrophage • vascular smooth muscle cell

Abbreviations and Acronyms   apoE = apolipoprotein E   BMDM = bone marrow-derived macrophage   BrdU = bromodeoxyuridine   GSNO = S-nitrosoglutathione   LDL = low-density lipoprotein   SM = smooth muscle   SNP = single nucleotide polymorphism   TUNEL = terminal deoxynucleotidyl transferase dUTP nick-end labeling   UV = ultraviolet light   VSMC = vascular smooth muscle cell

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