CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis
CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis
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CCN3 调节巨噬细胞泡沫细胞形成和动脉粥样硬化
DOI：
10.1016/j.ajpath.2017.01.020
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发表时间：
2017
影响因子：
6
通讯作者：
Lin Zhiyong
中科院分区：
文献类型：
--
作者：
Shi Hong;Zhang Chao;Pasupuleti Vinay;Hu Xingjian;Prosdocimo Domenick A.;Wu Wenconghui;Qing Yulan;Wu Shitong;Mohammad Haneen;Gerson Stanton L.;Perbal Bernard;Klenotic Philip A.;Dong Nianguo;Lin Zhiyong
最近的研究表明Cyr61、CTGF、Nov （CCN）基质细胞信号蛋白家族是血管生物学中的新兴成员，其中Nov（又称CCN3）是血管稳态的重要调节因子。在此，我们研究了CCN3在动脉粥样硬化发病机制中的作用。在15周的高脂肪饮食喂养中，与对照apoe - / -小鼠相比，动脉粥样硬化易感性apoe - / -背景的ccn3缺陷小鼠的主动脉富含脂质斑块增加，这一结果在血浆脂质含量没有改变的情况下观察到。为了解决细胞贡献者(s)负责动脉粥样硬化表型，我们进行了骨髓移植实验。移植ofApoe;ccn3双敲除骨髓移植到apoe−/−小鼠中导致动脉粥样硬化斑块负荷增加，而apoe−/−骨髓移植到apoe；ccn3双敲除小鼠导致动脉粥样硬化减少。这些结果表明，CCN3缺乏，特别是在骨髓中，在动脉粥样硬化的发展中起着重要作用。机制上，在分离的腹腔巨噬细胞中进行的基于细胞的研究表明，CCN3缺乏导致脂质摄取增加和泡沫细胞形成，这一效应可能归因于清除率受体CD36和SRA1的表达增加，这是参与脂蛋白摄取的关键因素。这些结果表明，骨髓来源的CCN3是动脉粥样硬化的重要调节剂，并指出CCN3在调节巨噬细胞内脂质积累中的新作用。
Recent studies implicate the Cyr61, CTGF, Nov (CCN) matricellular signaling protein family as emerging players in vascular biology, with NOV (alias CCN3) as an important regulator of vascular homeostasis. Herein, we examined the role of CCN3 in the pathogenesis of atherosclerosis. In response to a 15-week high-fat diet feeding, CCN3-deficient mice on the atherosclerosis-proneApoe−/−background developed increased aortic lipid-rich plaques compared to controlApoe−/−mice, a result that was observed in the absence of alterations in plasma lipid content. To address the cellular contributor(s) responsible for the atherosclerotic phenotype, we performed bone marrow transplantation experiments. Transplantation ofApoe;Ccn3double-knockout bone marrow intoApoe−/−mice resulted in an increase of atherosclerotic plaque burden, whereas transplantation ofApoe−/−marrow toApoe;Ccn3double-knockout mice caused a reduction of atherosclerosis. These results indicate that CCN3 deficiency, specifically in the bone marrow, plays a major role in the development of atherosclerosis. Mechanistically, cell-based studies in isolated peritoneal macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect potentially attributed to the increased expression of scavenger receptors CD36 and SRA1, key factors involved in lipoprotein uptake. These results suggest that bone marrow–derived CCN3 is an essential regulator of atherosclerosis and point to a novel role of CCN3 in modulating lipid accumulation within macrophages.