P2Y6 receptor potentiates pro-inflammatory responses in macrophages and exhibits differential roles in atherosclerotic lesion development.
P2Y6 receptor potentiates pro-inflammatory responses in macrophages and exhibits differential roles in atherosclerotic lesion development.
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DOI：
10.1371/journal.pone.0111385
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Gargalovic PS
中科院分区：
文献类型：
--
作者：
Garcia RA;Yan M;Search D;Zhang R;Carson NL;Ryan CS;Smith-Monroy C;Zheng J;Chen J;Kong Y;Tang H;Hellings SE;Wardwell-Swanson J;Dinchuk JE;Psaltis GC;Gordon DA;Glunz PW;Gargalovic PS
P2Y6是UDP的嘌呤能受体，在动脉粥样硬化病变中含量丰富，并参与关键血管细胞类型和巨噬细胞的促炎反应。然而，关于它参与动脉粥样硬化形成的证据一直很少。在这里，我们使用基于细胞的研究和三种小鼠动脉粥样硬化形成的模型来评估P2Y6缺乏对动脉粥样硬化的影响。在缺乏功能性P2Y6受体的1321N1星形细胞瘤细胞中进行的基于细胞的研究表明，外源表达P2Y6可以诱导依赖受体和激动剂的强健的炎性介质IL-8、IL-6、MCP-1和GRO1的分泌。在内源性表达P2Y6的巨噬细胞和炎症的急性腹膜炎模型中，也观察到了P2Y6介导的炎症反应，尽管程度较小。为了评估P2Y6在动脉粥样硬化病变发展中的作用，我们使用了三种动脉粥样硬化小鼠模型中的P2Y6缺陷小鼠。观察到，在骨髓来源细胞中缺乏P2Y6受体的高脂饮食LDLR基因敲除小鼠中，主动脉弓斑块减少了43%。相比之下，在脂肪喂养的全身P2Y6xLDLR双基因敲除小鼠中，没有观察到对病变发展的影响。有趣的是，在使用血管紧张素II增强血管炎症的模型中，在LDLR基因敲除的小鼠中，P2Y6缺乏促进了动脉瘤的形成，并显示出动脉粥样硬化增加的趋势。P2Y6受体增强巨噬细胞的促炎反应，并在造血细胞中表现出促动脉粥样硬化的作用。然而，全身缺乏P2Y6对动脉粥样硬化的总体影响似乎不大，可能反映了P2Y6在血管疾病病理生理学中的额外作用，如动脉瘤的形成。
P2Y6, a purinergic receptor for UDP, is enriched in atherosclerotic lesions and is implicated in pro-inflammatory responses of key vascular cell types and macrophages. Evidence for its involvement in atherogenesis, however, has been lacking. Here we use cell-based studies and three murine models of atherogenesis to evaluate the impact of P2Y6 deficiency on atherosclerosis. Cell-based studies in 1321N1 astrocytoma cells, which lack functional P2Y6 receptors, showed that exogenous expression of P2Y6 induces a robust, receptor- and agonist-dependent secretion of inflammatory mediators IL-8, IL-6, MCP-1 and GRO1. P2Y6-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y6 and in acute peritonitis models of inflammation. To evaluate the role of P2Y6 in atherosclerotic lesion development, we used P2Y6-deficient mice in three mouse models of atherosclerosis. A 43% reduction in aortic arch plaque was observed in high fat-fed LDLR knockout mice lacking P2Y6 receptors in bone marrow-derived cells. In contrast, no effect on lesion development was observed in fat-fed whole body P2Y6xLDLR double knockout mice. Interestingly, in a model of enhanced vascular inflammation using angiotensin II, P2Y6 deficiency enhanced formation of aneurysms and exhibited a trend towards increased atherosclerosis in the aorta of LDLR knockout mice. P2Y6 receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells. However, the overall impact of whole body P2Y6 deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y6 in vascular disease pathophysiologies, such as aneurysm formation.
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影响因子：
64.5
作者：
Moore KJ;Tabas I
通讯作者：
Tabas I
DOI：
10.1186/1745-7580-4-5
发表时间：
2008-04-29
期刊：
Immunome research
影响因子：
--
作者：
Lattin JE;Schroder K;Su AI;Walker JR;Zhang J;Wiltshire T;Saijo K;Glass CK;Hume DA;Kellie S;Sweet MJ
通讯作者：
Sweet MJ
影响因子：
4.4
作者：
Uratsuji, Hideya;Tada, Yayoi;Tamaki, Kunihiko
通讯作者：
Tamaki, Kunihiko
影响因子：
4.4
作者：
Kim, Beomsue;Jeong, Hey-kyeong;Joe, Eun-hye
通讯作者：
Joe, Eun-hye
影响因子：
10.8
作者：
Kauffenstein, Gilles;Drouin, Annick;Sevigny, Jean
通讯作者：
Sevigny, Jean