p19ARF Deficiency Reduces Macrophage and Vascular Smooth Muscle Cell Apoptosis and Aggravates Atherosclerosis
p19ARF Deficiency Reduces Macrophage and Vascular Smooth Muscle Cell Apoptosis and Aggravates Atherosclerosis
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DOI：
10.1016/j.jacc.2010.01.026
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发表时间：
2010-05-18
影响因子：
24
通讯作者：
Andres, Vicente
中科院分区：
文献类型：
--
作者：
Gonzalez-Navarro, Herminia;Abu Nabah, Yafa Naim;Andres, Vicente
目的研究CDKN 2A基因编码的抑癌蛋白ARF（human p14（ARF），mouse p19（ARF））在动脉粥样硬化（atherosclerosis，AS）中的作用。尽管最近的全基因组关联研究已经将动脉粥样硬化疾病与人类染色体9 p21中靠近CDKN 2A位点的基因组区域联系起来，但这种基因-疾病关联的机制仍然不确定，CDKN 2A和动脉粥样硬化之间没有因果关系。方法动脉粥样硬化倾向载脂蛋白E（apoE）-null和双重缺陷apoE-p19（ARF）给小鼠喂食致动脉粥样硬化饮食并处死以量化整体固定的动脉粥样硬化和主动脉横截面中的动脉粥样硬化负荷。增殖和凋亡进行了研究，在动脉粥样硬化病变和在原代培养的巨噬细胞和血管平滑肌细胞从两组mice. Resultsp 19（ARF）在apoE基因敲除小鼠增强主动脉粥样硬化，而不影响体重，血浆脂蛋白，或斑块的增殖活性。值得注意的是，p19（ARF）缺陷显着减弱细胞凋亡在动脉粥样硬化病变和培养的巨噬细胞和血管平滑肌细胞，2个主要的细胞成分动脉粥样硬化plaques.ConclusionsOur研究结果建立了直接联系p19（ARF），斑块凋亡，动脉粥样硬化，并表明，人类基因变异相关的CDKN 2A表达减少可能会加速动脉粥样硬化斑块凋亡限制。（J Am科尔心脏病学杂志2010;55：2258-68）（C）美国心脏病学会基金会2010年
ObjectivesThe 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.BackgroundAtherosclerosis 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.MethodsAtherosclerosis-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.ResultsGenetic 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.ConclusionsOur 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. (J Am Coll Cardiol 2010;55:2258-68) (C) 2010 by the American College of Cardiology Foundation