Haider Asifa, Olszanecki Rafal, Gryglewski Richard, Schwartzman Michal L, Lianos Elias, Kappas Attallah, Nasjletti Alberto, Abraham Nader G
New York Medical College, Department of Pharmacology, Valhalla, New York 10595, USA.
J Pharmacol Exp Ther. 2002 Jan;300(1):188-94. doi: 10.1124/jpet.300.1.188.
Heme oxygenase (HO) is a microsomal enzyme that oxidatively cleaves heme to form biliverdin, with the release of iron and carbon monoxide (CO). HO not only controls the availability of heme for the synthesis of heme proteins but also is responsible for the generation of CO, which binds to the heme moiety of heme proteins thus affecting their enzymatic activity. Cyclooxygenase (COX) is a heme protein that catalyzes the conversion of arachidonic acid to prostaglandin H(2), the precursor of prostanoids that participate in the regulation of vascular function. The goal of the present study was to determine whether the heme-HO system regulates COX enzyme expression and activity in vascular endothelial cells. Endothelial cells stably transfected with the human HO-1 gene exhibited a severalfold increase in human HO-1 mRNA levels, which was accompanied by an increase in HO activity and a marked decrease in prostaglandin (PG) E(2) and 6-keto-PGF(1alpha) levels. Exposure of cells to CoCl(2), an inducer of HO-1 gene expression, resulted in increases in HO-1 protein levels and HO activity. The increase in HO activity was associated with a subsequent decrease in COX activity, which returned to normal levels following normalization of HO activity. The addition of heme resulted in an increase in COX activity with an increase in PGE(2) and 6-keto-PGF(1alpha) levels. The degree of HO-1 expression and, consequently, the level of cellular heme, were directly related to COX activity. These results demonstrate that the heme-HO system can function as a cellular regulator of the expression of vascular COX, thus influencing the generation of prostanoids, PGE(2) and PGI(2), known to play a role in vascular homeostasis.
血红素加氧酶（HO）是一种微粒体酶，可氧化裂解血红素形成胆绿素，并释放铁和一氧化碳（CO）。HO不仅控制血红素用于合成血红素蛋白的可用性，还负责生成CO，CO与血红素蛋白的血红素部分结合，从而影响其酶活性。环氧化酶（COX）是一种血红素蛋白，催化花生四烯酸转化为前列腺素H2，前列腺素是参与血管功能调节的前列腺素类的前体。本研究的目的是确定血红素-HO系统是否调节血管内皮细胞中COX酶的表达和活性。稳定转染人HO-1基因的内皮细胞中人HO-1 mRNA水平增加了几倍，同时伴随着HO活性的增加以及前列腺素（PG）E2和6-酮-PGF1α水平的显著降低。将细胞暴露于HO-1基因表达诱导剂氯化钴（CoCl2），导致HO-1蛋白水平和HO活性增加。HO活性的增加与随后COX活性的降低相关，HO活性恢复正常后，COX活性也恢复到正常水平。添加血红素导致COX活性增加，同时PGE2和6-酮-PGF1α水平增加。HO-1的表达程度以及细胞血红素水平与COX活性直接相关。这些结果表明，血红素-HO系统可作为血管COX表达的细胞调节剂，从而影响前列腺素PGE2和前列环素PGI2的生成，已知它们在血管稳态中发挥作用。
