Cyclooxygenase-2 inhibition increases lipopolysaccharide-induced atherosclerosis in mice
Cyclooxygenase-2 inhibition increases lipopolysaccharide-induced atherosclerosis in mice
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DOI：
10.1093/cvr/cvn286
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发表时间：
2009-02-01
影响因子：
10.8
通讯作者：
Loftin, Charles D.
中科院分区：
文献类型：
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作者：
Gitlin, Jonathan M.;Loftin, Charles D.
长期使用环氧合酶-2（考克斯-2）抑制剂会增加人类不良心血管事件的风险。然而，考克斯-2在心血管疾病动物模型中的作用一直存在争议。在人类和动物模型中，牙齿支持组织的细菌感染会增加心血管疾病，这种情况称为牙周病。牙周病可能导致慢性暴露于促炎介质，如细菌脂多糖（LPS），从而产生全身炎症反应。本研究旨在探讨考克斯-2在牙周病病原菌牙龈卟啉单胞菌（Porphyromonas gingivalis，P. gingivalis）LPS诱导动脉粥样硬化中的作用。比较接受对照饮食或含有考克斯-2抑制剂塞来昔布饮食的小鼠之间动脉粥样硬化的程度。在腹腔巨噬细胞中检测考克斯-2在牙龈卟啉单胞菌LPS诱导的炎性细胞活化中的作用。牙龈卟啉单胞菌LPS输注显著增加动脉粥样硬化的发展。在输注牙龈卟啉单胞菌LPS的小鼠中，给予考克斯-2抑制剂塞来昔布进一步增加了动脉粥样硬化病变面积的程度。牙龈卟啉单胞菌脂多糖可增加巨噬细胞考克斯-2 mRNA表达和前列腺素E-2（PGE（2））的生成，而塞来昔布可抑制前列腺素E-2的生成。牙龈卟啉单胞菌LPS诱导的肿瘤坏死因子α（TNF α）表达可通过考克斯-2的失活而增强，而PGE（2）可减弱其表达。抑制考克斯-2衍生的PGE（2）可通过增加巨噬细胞TNF α的产生而增强牙龈卟啉单胞菌LPS诱导的动脉粥样硬化。
The risk of adverse cardiovascular events in humans is increased with chronic use of cyclooxygenase-2 (COX-2) inhibitors. However, the role of COX-2 in animal models of cardiovascular disease has been controversial. In humans and animal models, cardiovascular disease is increased by bacterial infection of the supporting tissue of the teeth, a condition known as periodontal disease. Periodontal disease may result in chronic exposure to pro-inflammatory mediators, such as bacterial lipopolysaccharide (LPS), thereby producing a systemic inflammatory response. The current study examined the role of COX-2 in atherosclerosis induced by LPS derived from the periodontal disease pathogen Porphyromonas gingivalis (P. gingivalis).Porphyromonas gingivalis LPS was administered by chronic infusion for 28 days and atherosclerosis development was examined in the aortic root of ApoE (apolipoprotein E)-deficient mice. The extent of atherosclerosis was compared between mice receiving control diet or diet containing the COX-2 inhibitor celecoxib. The role of COX-2 in P. gingivalis LPS-induced inflammatory cell activation was examined in peritoneal macrophages. Porphyromonas gingivalis LPS infusion significantly increased atherosclerosis development. In mice infused with P. gingivalis LPS, administration of the COX-2 inhibitor celecoxib further increased the extent of atherosclerotic lesion area. In peritoneal macrophages, P. gingivalis LPS increased the expression of COX-2 mRNA (messenger ribonucleic acid) and the production of prostaglandin (PG) E-2 (PGE(2)), the latter of which was inhibited by celecoxib. Porphyromonas gingivalis LPS-induced expression of tumour necrosis factor alpha (TNF alpha) was enhanced by inactivation of COX-2 and was attenuated by treatment with PGE(2).The inhibition of COX-2-derived PGE(2) may enhance P. gingivalis LPS-induced atherosclerosis by increasing macrophage production of TNF alpha.