COX-2 Protects against Atherosclerosis Independently of Local Vascular Prostacyclin: Identification of COX-2 Associated Pathways Implicate Rgl1 and Lymphocyte Networks

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.

环氧合酶-2（cyclooxygenase-2, COX-2）抑制剂，包括传统非甾体抗炎药（nonsteroidal anti-inflammatory drugs, NSAIDs），均与包括心肌梗死在内的心血管不良反应风险升高相关。我们及其他研究团队已证实，在健康心血管系统中，环氧合酶-1（cyclooxygenase-1, COX-1）而非COX-2介导血管前列环素的生成，这重新开启了关于COX-2如何调控心血管健康的学术议题。在患病的动脉粥样硬化血管中，COX-2对前列环素生成的相对贡献尚不明确。本研究利用apoE−/−/COX-2−/−双基因敲除小鼠展开实验，结果显示尽管COX-2可显著抑制动脉粥样硬化进程，但这种保护作用并不依赖于局部前列环素的释放。上述数据进一步表明，我们需要探索新的解释机制、干预靶点与信号通路，以明确COX/NSAID/心血管风险这一关联轴。对apoE−/−/COX-2−/−小鼠组织的基因表达谱分析显示，淋巴细胞相关通路出现激活，这一结果通过斑块内T淋巴细胞浸润增加以及血浆中Th1型细胞因子水平升高得到了验证。此外，本研究还鉴定出一个全新的靶基因rgl1，在所有检测的组织中，COX-2缺失都会使其表达水平显著下调。本研究首次证实，COX-2可独立于局部血管前列环素的生成，发挥对抗动脉粥样硬化病变的血管保护作用，并通过系统生物学方法挖掘出与新一代非甾体抗炎药开发相关的全新机制。