COX-2 protects against atherosclerosis independently of local vascular prostacyclin: identification of COX-2 associated pathways implicate Rgl1 and lymphocyte networks.
COX-2 protects against atherosclerosis independently of local vascular prostacyclin: identification of COX-2 associated pathways implicate Rgl1 and lymphocyte networks.
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DOI：
10.1371/journal.pone.0098165
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Mitchell JA
中科院分区：
文献类型：
--
作者：
Kirkby NS;Lundberg MH;Wright WR;Warner TD;Paul-Clark MJ;Mitchell JA
环氧合酶(COX)-2抑制剂，包括传统的非类固醇抗炎药(NSAIDs)，与包括心肌梗死在内的心血管副作用增加有关。我们和其他人已经证明，COX-1而不是COX-2在健康的心血管系统中驱动血管前列环素，重新打开了COX-2可能如何调节心血管健康的问题。在病变的动脉粥样硬化的血管中，COX-2对前列环素形成的相对贡献尚不清楚。在这里，我们使用载脂蛋白E−/−/COX-2−/−小鼠来证明，虽然COX-2深刻地限制了动脉粥样硬化，但这种保护是独立于局部前列环素的释放的。这些数据进一步说明，需要寻找新的解释、靶点和途径来定义COX/NSAID/心血管风险轴。载脂蛋白E−/−/COX-2−/−小鼠组织中的基因表达谱显示淋巴细胞途径增加，斑块中T淋巴细胞增加和血浆Th1型细胞因子增加证实了这一点。此外，我们确定了一个新的靶基因rgl1，它的表达因COX-2的缺失而在所有被检查的组织中显著降低。这项研究首次证明COX-2独立于局部血管前列环素保护血管免受动脉粥样硬化损害，并使用系统生物学方法确定与下一代非类固醇抗炎药发展相关的新机制。
Cyxlo-oxygenase (COX)-2 inhibitors, including traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased cardiovascular side effects, including myocardial infarction. We and others have shown that COX-1 and not COX-2 drives vascular prostacyclin in the healthy cardiovascular system, re-opening the question of how COX-2 might regulate cardiovascular health. In diseased, atherosclerotic vessels, the relative contribution of COX-2 to prostacyclin formation is not clear. Here we have used apoE−/−/COX-2−/− mice to show that, whilst COX-2 profoundly limits atherosclerosis, this protection is independent of local prostacyclin release. These data further illustrate the need to look for new explanations, targets and pathways to define the COX/NSAID/cardiovascular risk axis. Gene expression profiles in tissues from apoE−/−/COX-2−/− mice showed increased lymphocyte pathways that were validated by showing increased T-lymphocytes in plaques and elevated plasma Th1-type cytokines. In addition, we identified a novel target gene, rgl1, whose expression was strongly reduced by COX-2 deletion across all examined tissues. This study is the first to demonstrate that COX-2 protects vessels against atherosclerotic lesions independently of local vascular prostacyclin and uses systems biology approaches to identify new mechanisms relevant to development of next generation NSAIDs.
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影响因子：
37.8
作者：
Hui Y;Ricciotti E;Crichton I;Yu Z;Wang D;Stubbe J;Wang M;Puré E;FitzGerald GA
通讯作者：
FitzGerald GA
影响因子：
10.8
作者：
Gitlin, Jonathan M.;Loftin, Charles D.
通讯作者：
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DOI：
10.1161/atvbaha.107.149476
发表时间：
2007-11-01
影响因子：
8.7
作者：
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通讯作者：
Dengler, Thomas J.
影响因子：
8.7
作者：
Baker, CSR;Hall, RJC;Polak, JM
通讯作者：
Polak, JM
影响因子：
37.8
作者：
Barbieri, Silvia S.;Amadio, Patrizia;Tremoli, Elena
通讯作者：
Tremoli, Elena