ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice
ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice
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DOI：
10.1182/blood-2011-09-376202
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发表时间：
2012-03-08
期刊：
影响因子：
20.3
通讯作者：
Chauhan, Anil K.
中科院分区：
文献类型：
--
作者：
Gandhi, Chintan;Khan, Mohammad Moshahid;Chauhan, Anil K.
ADAMTS 13是一种金属蛋白酶，通过将过度活跃的超大型血管性血友病因子多聚体切割成较小、活性较低的多聚体，在预防自发性微血管血栓形成中发挥关键作用。血浆中ADAMTS 13活性降低已在许多与全身性炎症相关的疾病中描述。然而，ADAMTS 13是否有助于疾病的发病机制，或者只是作为炎症相关的标志物，仍然不确定。我们假设，通过减少血管炎症，ADAMTS 13减少早期动脉粥样硬化斑块的发展。使用活体荧光显微镜，我们观察到Adamts 13（-/-）/ApoE（-/-）小鼠与喂食高脂西方饮食的ApoE（-/-）小鼠相比，颈动脉窦处白细胞粘附过多，动脉粥样硬化斑块形成加速。在4月龄时，与ApoE（-/-）小鼠相比，Adamts 13（-/-）/ApoE（-/-）小鼠的主动脉和主动脉窦中的动脉粥样硬化显著增加。有趣的是，我们检测到Adamts 13（-/-）/ApoE（-/-）小鼠的动脉粥样硬化斑块中巨噬细胞募集量比ApoE（-/-）小鼠增加了2倍，这表明这些小鼠的动脉粥样硬化病变不仅更大，而且更具炎症性。这些发现揭示了抗血栓酶ADAMTS 13在减少早期动脉粥样硬化期间过度血管炎症和斑块形成方面的新功能作用。（血。2012;119（10）：2385-2391）
ADAMTS13, a metalloprotease, plays a pivotal role in preventing spontaneous microvascular thrombosis by cleaving hyperactive ultra large von Willebrand factor multimers into smaller, less active multimers. Reduced ADAMTS13 activity in plasma has been described in many diseases associated with systemic inflammation. It remains uncertain, however, whether ADAMTS13 contributes to disease pathogenesis or rather simply serves as an inflammation-associated marker. We hypothesized that, by decreasing vascular inflammation, ADAMTS13 reduces the development of early atherosclerotic plaques. Using intravital fluorescence microscopy, we observed excessive leukocyte adhesion and accelerated atherosclerotic plaque formation at the carotid sinus of Adamts13(-/-)/ApoE(-/-) mice compared with ApoE(-/-) mice fed a high-fat Western diet. At 4 months of age, there was a significant increase in atherosclerosis in the aorta and aortic sinus of Adamts13(-/-)/ApoE(-/-) mice compared with ApoE(-/-) mice. Interestingly, we detected a 2-fold increase in macrophage recruitment to the atherosclerotic plaque of the Adamts13(-/-)/ApoE(-/-) mice compared with ApoE(-/-) mice, suggesting that the atherosclerotic lesions in these mice were not only larger but also more inflammatory. These findings reveal a new functional role for the antithrombotic enzyme ADAMTS13 in reducing excessive vascular inflammation and plaque formation during early atherosclerosis. (Blood. 2012;119(10):2385-2391)