The ARF gene plays a role in atherosclerosis through the regulation of apoptosis in macrophages and vascular smooth muscle cells

J Am Coll Cardiol - May 18 2010

The identification of new cardiovascular risk factors, both environmental and genetic, is a major challenge in biomedical research. Genetic factors are estimated to account for 50% of the susceptibility to atherosclerosis and associated cardiovascular disease. Recent studies have identified a cluster of single nucleotide polymorphisms (SNPs) associated with risk of coronary arteriosclerosis and myocardial infarction. This association is strong, highly reproducible and independent of the "classic" cardiovascular risk factors such as dyslipidemia, hypertension, diabetes and obesity. It has been suggested that these SNPs, located in an intergenic region in chromosome 9p21, might influence the risk of atherosclerosis by regulating the expression of the INK4 and ARF genes, located in a nearby region of the same chromosome.

The study, which was carried out at the CNIC and the Instituto de Biomedicina de Valencia (CSIC) by Dr. Vicente Andrés's team in collaboration with the group of Dr. Manuel Serrano (CNIO), sheds light on the molecular mechanisms by which these SNPs in chromosome 9p21 are associated with the risk of atherosclerosis. Using genetically modified mice generated and characterized for the study, the team showed that the absence of p19ARF accelerates the development of atherosclerosis. Atherosclerosis is a chronic inflammatory process, and given that the INK4 and ARF genes regulate complex cellular processes involved in the disease, such as cell proliferation and apoptosis, the team examined the role of p19ARF in these processes, both in atherosclerotic plaques and in cultured macrophages and vascular smooth muscle cells (VSMCs), cell types that play key roles in all stages of disease development. The team found that the absence of p19ARF inhibits the apoptosis of these cells in the atherosclerotic plaque and accelerates disease development, without affecting cell proliferation in the lesions and independently of the levels of circulating lipids. Furthermore, macrophages and VSMCs from mice lacking p19ARF are resistant to apoptosis induced by various proapoptotic stimuli.
 

Another notable finding is that the proatherogenic effect associated with the absence of p19ARF is observed only in regions of the aorta that are highly susceptible to the development of atherosclerotic plaques, suggesting that ARF primarily affects the progression but not the initiation of atherosclerosis.

As noted by Dr. Rainer Wessely in his editorial in the same issue of The Journal of the American College of Cardiology, the paper reveals a hitherto undefined role of p19ARF in atherosclerosis. The results suggest that SNPs in chromosome 9p21 associated with reduced expression of ARF might accelerate atherosclerosis by decreasing apoptosis in the plaque. These findings are significant considering that approximately 25% of the population carries two copies of risk alleles in chromosome 9p21, doubling their risk of atherosclerosis compared with the non-carrying population. The identified polymorphic variants are also associated with risk of stroke, peripheral arterial disease and intracranial and abdominal aortic aneurysm. It is likely that future studies into the role of the INK4 and ARF genes and the proteins they encode will continue to shed light on the molecular-genetic mechanisms that govern arteriosclerosis and determine the individual risk of suffering from this disease. In particular, it will be of great interest to investigate the role of p15INK4b, p16INK4a and ANRIL, and whether the inactivation of two or more of these INK4/ARF-locus encoded proteins exacerbates atherosclerosis more than the lack of just one of them. These functional studies, together with additional genetic analysis of the affected region of chromosome 9p21, promise to facilitate both the development of new tools for early diagnosis of individuals at high cardiovascular risk and the identification of therapeutic targets to combat the leading cause of death and disability in the world.

p19(ARF) Deficiency Reduces Macrophage and Vascular Smooth Muscle Cell Apoptosis and Aggravates Atherosclerosis.
González-Navarro H, Naim Abu Nabah Y, Vinué A, Andrés-Manzano MJ, Collado M, Serrano M, Andrés V.

J Am Coll Cardiol. 2010 Mar 11