ROLE OF CYCLOOXYGENASE-2 IN CARDIOVASCULAR SYSTEM

环氧合酶-2(COX-2)是前列腺素(PG)的限速酶，在炎症、肿瘤的发生、发展和循环稳态中起着关键作用。PgD_2代谢产物15-Deoxy-Δ^&lt；12，14&gt；PgJ_2(15d-PgJ_2)是过氧化体增殖物激活受体-γ(PPARγ)的天然配体。在巨噬细胞中表达的PPARγ被认为是炎症的负性调节因子和与动脉粥样硬化相关的向泡沫细胞分化的正性调节因子。在此，我们发现15d-PGJ_2抑制脂多糖(LPS)诱导的巨噬细胞样分化的U937细胞中COX-2的表达，但对血管内皮细胞无影响。相反，脂多糖上调糖皮质激素受体γ的表达，其配体抗炎类固醇地塞米松可强烈抑制脂多糖诱导的COX-2基因的表达，而15d-κ_2和地塞米松通过干扰NF-PGEB信号通路抑制COX-2启动子的活性。将PPARγ表达载体导入内皮细胞，可被15d-pGJ_2抑制COX-2基因的表达，但不能被DEX抑制。选择性COX-2抑制剂NS-398可抑制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PPARγ介导的负反馈环的调节，这使得PG的动态产生成为可能，尤其是在巨噬细胞中，这可能归因于COX-2的多种表达模式和生理功能。

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.