ROLE OF CYCLOOXYGENASE-2 IN CARDIOVASCULAR SYSTEM

环加氧酶-2 在心血管系统中的作用

基本信息

批准号：
11838021
负责人：
INOUE Hiroyasu
金额：
$ 2.18万
依托单位：
NATIONAL CARDIOVASCULAR CENTER RESEARCH INSTITUTE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Cyclooxygenase-2(COX-2), a rate-limiting enzyme for prostaglandins(PG), plays a key role in inflammation, tumorigenesis, development and circulatory homeostasis. The PGD_2 metabolite 15-deoxy-Δ^<12,14>PGJ_2(15d-PGJ_2) was identified as a potent natural ligand for the peroxisome proliferator-activated receptor-γ(PPARγ). PPARγ expressed in macrophages has been postulated as a negative regulator of inflammation and a positive regulator of differentiation into foam cell associated with atherogenesis. Here we show that 15d-PGJ_2 suppresses the lipopolysaccharide(LPS)-induced expression of COX-2 in the macrophage-like differentiated U937 cells but not in vascular endothelial cells. PPARγ mRNA abundantly expressed in the U937 cells not in the endothelial cells is down-regulated by LPS.In contrast, LPS up-regulates mRNA for the glucocorticoid receptor which ligand anti-inflammatory steroid dexamethasone(DEX) strongly suppresses the LPS-induced expression of COX-2 gene although both 15d-PGJ_2 and DEX suppressed COX-2 promoter activity by interfering with the NF-κB signaling pathway. Transfection of a PPARγ-expression vector into the endothelial cells acquires this suppressive regulation of COX-2 gene by 15d-PGJ_2 but not by DEX.A selective COX-2 inhibitor NS-398 inhibits production of PGD_2 in the U937 cells. Taken together, we propose that expression of COX-2 will be regulated by a negative feedback loop mediated through PPARγ, which makes possible a dynamic production of PG, especially in macrophages, and may be attributed to various expression patterns and physiological functions of COX-2.

环加氧酶-2(COX-2)是前列腺素(PG)的限速酶，在炎症、肿瘤发生、发育和循环稳态中发挥关键作用，PGD_2代谢物15-脱氧-Δ^<12,14>PGJ_2( 15d-PGJ_2) 被鉴定为过氧化物酶体增殖物激活受体-γ (PPARγ) 的有效天然配体。巨噬细胞中表达的 PPARγ 被认为是炎症的负调节剂和与动脉粥样硬化形成相关的泡沫细胞分化的正调节剂。在此，我们表明 15d-PGJ_2 抑制脂多糖 (LPS) 诱导的巨噬细胞中 COX-2 的表达。与分化的 U937 细胞相似，但不在血管内皮细胞中表达。 PPARγ mRNA 在 U937 细胞中大量表达，但在内皮细胞中不表达。 LPS 下调。相反，LPS 上调糖皮质激素受体的 mRNA，该受体配体抗炎类固醇地塞米松 (DEX) 抑制 LPS 诱导的 COX-2 基因表达，尽管 15d-PGJ_2 和 DEX 均抑制 COX-2通过干扰 NF-κB 信号通路来调节启动子活性，将 PPARγ 表达载体转染到内皮细胞中，获得这种抑制性调节。 COX-2 基因受 15d-PGJ_2 影响，但不受 DEX 影响。选择性 COX-2 抑制剂 NS-398 抑制 U937 细胞中 PGD_2 的产生。综上所述，我们认为 COX-2 的表达将受到负反馈环的调节。通过 PPARγ 介导，这使得 PG 的动态产生成为可能，尤其是在巨噬细胞中，并且可能归因于 COX-2 的各种表达模式和生理功能。