Regulation of inducible nitric oxide synthase expression in advanced glycation end product-stimulated raw 264.7 cells: the role of heme oxygenase-1 and endogenous nitric oxide.
Regulation of inducible nitric oxide synthase expression in advanced glycation end product-stimulated raw 264.7 cells: the role of heme oxygenase-1 and endogenous nitric oxide.
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DOI：
10.2337/diabetes.53.7.1841
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发表时间：
2004-07
期刊：
影响因子：
7.7
通讯作者：
D. Sumi;L. Ignarro
中科院分区：
文献类型：
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作者：
D. Sumi;L. Ignarro
糖基化终末产物（AGEs）与糖尿病动脉粥样硬化的发生密切相关。目前的研究探讨诱导型一氧化氮（NO）合酶（iNOS）和血红素加氧酶（HO）-1表达AGEs的诱导，以及参与的信号通路和这两种酶之间的相互作用。用6.64或33.2 μ g/ml AGEs刺激RAW 264.7细胞导致HO-1蛋白表达、iNOS蛋白表达和亚硝酸盐积累。AGEs导致p42/44和p38丝裂原活化蛋白激酶（MAPK）的磷酸化。p42/44 MAPK和蛋白激酶C的抑制阻止了AGE诱导的亚硝酸盐释放和iNOS表达，而p38 MAPK的抑制增强了AGE诱导的亚硝酸盐释放和iNOS表达。与此相反，HO-1的表达下调抑制p38 MAPK。此外，这两种蛋白质的表达被阻止与乙酰香草酮（NADPH氧化酶抑制剂）共孵育。镉或内源性NO刺激HO-1表达可负调节AGE诱导的iNOS表达。锡原卟啉IX（HO-1抑制剂）可部分逆转镉介导的iNOS表达下调。目前的研究表明，多种信号分子参与了AGE刺激的iNOS和HO-1的表达。也存在iNOS自身产物以及HO-1产物对iNOS的下调。
Advanced glycation end products (AGEs) are closely linked to the development of diabetic atherosclerosis. The current study examines the induction of inducible nitric oxide (NO) synthase (iNOS) and heme oxygenase (HO)-1 expression by AGEs, as well as the signaling pathways involved and the interplay between these two enzymes. The stimulation of RAW 264.7 cells with 6.64 or 33.2 microg/ml AGEs leads to HO-1 protein expression, iNOS protein expression, and nitrite accumulation. AGEs lead to the phosphorylation of p42/44 and p38 mitogen-activated protein kinase (MAPK). The inhibition of p42/44 MAPK and protein kinase C prevented, whereas inhibition of p38 MAPK augmented, AGE-induced nitrite release and iNOS expression. In contrast, HO-1 expression was downregulated by inhibition of p38 MAPK. Furthermore, the expression of both proteins was prevented by coincubation with acetovanillone (NADPH oxidase inhibitor). AGE-induced iNOS expression was negatively regulated by stimulation of HO-1 expression with cadmium chloride or endogenous NO. Tin-protoporphyrin IX (HO-1 inhibitor) partially reversed the cadmium chloride-mediated downregulation of iNOS expression. The current study demonstrates that multiple signaling molecules are involved in AGE-stimulated iNOS and HO-1 expression. There also exists a downregulation of iNOS by its own product as well as the products of HO-1.