The anti-inflammatory vasostatin-2 attenuates atherosclerosis in ApoE-/- mice and inhibits monocyte/macrophage recruitment
The anti-inflammatory vasostatin-2 attenuates atherosclerosis in ApoE-/- mice and inhibits monocyte/macrophage recruitment
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DOI：
10.1160/th16-06-0475
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发表时间：
2016-11
影响因子：
6.7
通讯作者：
Weixin Xiong;Xiaoqun Wang;Daopeng Dai;Bao Zhang;Lin Lu;R. Tao
中科院分区：
文献类型：
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作者：
Weixin Xiong;Xiaoqun Wang;Daopeng Dai;Bao Zhang;Lin Lu;R. Tao
我们之前的研究表明，血管抑素-2 （VS-2）水平的降低与冠状动脉疾病的存在和严重程度相关。在本研究中，我们旨在了解色粒蛋白A （CGA）衍生的VS-2在动脉粥样硬化的发展和单核/巨噬细胞募集中的作用。高脂饲料喂养的载脂蛋白e缺乏（ApoE-/-）小鼠，VS-2治疗组与PBS组相比，enface和主动脉根部油红O染色的病变面积分别缩小65%和41%，MOMA-2阳性面积分别缩小64%。促炎因子肿瘤坏死因子-α (TNF-α)、单核细胞趋化蛋白-1 （MCP-1）和血管细胞粘附分子-1 （VCAM-1）在VS-2治疗后均显著降低。机制上，在活体显微镜下的黏附实验中，VS-2抑制了apoE-/-小鼠肠系膜动脉壁上的白细胞数量。趋化实验中，对C57BL/6小鼠腹腔灌洗液的流式细胞术分析显示，VS-2显著降低巯基乙酸酯诱导的腹膜炎模型中炎性单核/巨噬细胞的募集数量。此外，经VS-2治疗后，apoE-/-小鼠主动脉窦病变中标记Ly-6Chi单核细胞的荧光乳胶珠较少。此外，根据人单核/巨噬细胞微阵列，我们发现VS-2刺激引起小鼠原代单核细胞和THP-1细胞中Rac1表达和Pak1失活的剂量依赖性降低，并抑制MCP-1/CCL-5诱导的体外迁移。综上所述，嗜铬粒蛋白a衍生的VS-2可以减轻apoE-/-小鼠的动脉粥样硬化，除了具有抗炎特性外，还可以抑制单核细胞/巨噬细胞的募集。本文的补充材料可在www.thrombosis-online.com上在线获得。
Summary We showed previously that reduced level of vasostatin-2 (VS-2) correlates to the presence and severity of coronary artery disease. In this study, we aimed to figure out the role of chromogranin A (CGA) derived VS-2 in the development of atherosclerosis and monocyte/macrophage recruitment. Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet exhibited attenuated lesion size by 65 % and 41 % in En face and aortic root Oil red O staining, MOMA-2 positive area by 64 %, respectively, in VS-2 treatment group compared with PBS group. Proinflammatory cytokines tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) were all remarkably reduced in aortic tissues after VS-2 treatment. Mechanistically, in adhesion assay using intravital microscopy in vivo, VS-2 suppressed the number of leukocytes adhering to the wall of apoE-/- mice mesenteric arteries. In chemotactic assay, flow cytometry analysis of peritoneal lavage exudate from C57BL/6 mice showed VS-2 significantly decreased the recruiment number of inflammatory monocytes/macrophages in a thioglycollate-induced peritonitis model. Furthermore, fewer fluorescent latex beads labelled Ly-6Chi monocytes accumulated in aortic sinus lesions of apoE-/- mice after VS-2 treatment. In addition, according to the microarray of human monocyte/macrophage, we found VS-2 stimulation caused a dose-dependent decrease of Rac1 expression and inactivation of Pak1 in mice primary monocytes as well as THP-1 cells and inhibited MCP-1/CCL-5 induced transmigration in vitro. In conclusion, the Chromogranin A-derived VS-2 attenuates atherosclerosis in apoE-/- mice and, in addition to its anti-inflammatory property, also acts as an inhibitor in monocyte/macrophage recruitment. Supplementary Material to this article is available online at www.thrombosis-online.com.