Loss of Apoptosis Regulator through Modulating IAP Expression (ARIA) Protects Blood Vessels from Atherosclerosis
Loss of Apoptosis Regulator through Modulating IAP Expression (ARIA) Protects Blood Vessels from Atherosclerosis
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DOI：
10.1074/jbc.m114.605287
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发表时间：
2015-02-06
影响因子：
4.8
通讯作者：
Ikeda, Koji
中科院分区：
文献类型：
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作者：
Matsuo, Kiyonari;Akakabe, Yoshiki;Ikeda, Koji
动脉粥样硬化是心血管疾病的主要原因。在这里，我们确定了动脉粥样硬化的一种新机制，这是由我们最近发现的跨膜蛋白ARIA（通过调节IAP表达的凋亡调节因子）提供的。ARIA在人动脉粥样硬化斑块中存在的巨噬细胞以及小鼠腹膜巨噬细胞中表达。当用乙酰化LDL挑战时，从ARIA缺陷小鼠中分离的腹腔巨噬细胞显示泡沫细胞形成显著减少，而摄取与野生型巨噬细胞没有差异。从机制上讲，ARIA的缺失增强了PI 3 K/Akt信号传导，从而降低了酰基辅酶A：胆固醇酰基转移酶-1（ACAT-1）的表达，ACAT-1是一种使胆固醇变性并促进其储存的酶。PI 3 K的抑制消除了ARIA缺陷型巨噬细胞中ACAT-1表达和泡沫细胞形成的减少。相反，ARIA的过表达降低了RAW264.7巨噬细胞中Akt的活性，并增强了泡沫细胞的形成，这被ACAT抑制剂处理所消除。值得注意的是，ARIA的基因缺失显著降低了ApoE缺陷小鼠的动脉粥样硬化。ARIA/ApoE双缺陷小鼠动脉粥样硬化斑块中油红O阳性的富脂病变减少，胶原纤维增加，坏死核心病变减少。对骨髓嵌合小鼠的分析表明，骨髓细胞中ARIA的缺失足以减少ApoE缺陷小鼠的动脉粥样硬化形成。总之，我们确定了ARIA在动脉粥样硬化发病机制中的独特作用，至少部分是通过调节巨噬细胞泡沫细胞的形成。我们的研究结果表明，ARIA可以作为一个新的药物治疗动脉粥样硬化性疾病的目标。
Atherosclerosis is the primary cause for cardiovascular disease. Here we identified a novel mechanism underlying atherosclerosis, which is provided by ARIA (apoptosis regulator through modulating IAP expression), the transmembrane protein that we recently identified. ARIA is expressed in macrophages present in human atherosclerotic plaque as well as in mouse peritoneal macrophages. When challenged with acetylated LDL, peritoneal macrophages isolated from ARIA-deficient mice showed substantially reduced foam cell formation, whereas the uptake did not differ from that in wild-type macrophages. Mechanistically, loss of ARIA enhanced PI3K/Akt signaling and consequently reduced the expression of acyl coenzyme A: cholesterol acyltransferase-1 (ACAT-1), an enzyme that esterifies cholesterol and promotes its storage, in macrophages. Inhibition of PI3K abolished the reduction in ACAT-1 expression and foam cell formation in ARIA-deficient macrophages. In contrast, overexpression of ARIA reduced Akt activity and enhanced foam cell formation in RAW264.7 macrophages, which was abrogated by treatment with ACAT inhibitor. Of note, genetic deletion of ARIA significantly reduced the atherosclerosis in ApoE-deficient mice. Oil red-O-positive lipid-rich lesion was reduced, which was accompanied by an increase of collagen fiber and decrease of necrotic core lesion in atherosclerotic plaque in ARIA/ApoE double-deficient mice. Analysis of bone marrow chimeric mice revealed that loss of ARIA in bone marrow cells was sufficient to reduce the atherosclerogenesis in ApoE-deficient mice. Together, we identified a unique role of ARIA in the pathogenesis of atherosclerosis at least partly by modulating macrophage foam cell formation. Our results indicate that ARIA could serve as a novel pharmacotherapeutic target for the treatment of atherosclerotic diseases.