AZD3582 increases heme oxygenase-1 expression and antioxidant activity in vascular endothelial and gastric mucosal cells
AZD3582 increases heme oxygenase-1 expression and antioxidant activity in vascular endothelial and gastric mucosal cells
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DOI：
10.1016/j.ejps.2005.02.015
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发表时间：
2005-06-01
影响因子：
4.6
通讯作者：
Schröder, H
中科院分区：
文献类型：
--
作者：
Berndt, G;Grosser, N;Schröder, H
AZD 3582 [4-（nitrooxy）-butyl-（2S）-2-（6-methoxy-2-naphthyl）-propanoate]是一种COX抑制型一氧化氮供体（CINOD）。用AZD 3582（10-100 μ M）孵育人内皮细胞（来自脐带）导致血红素加氧酶（HO）-1 mRNA和蛋白质表达增加。血红素氧合酶-1（HO-1）是抗氧化和组织保护作用的重要介质。与此相反，萘普生（非选择性NSAID）和罗非昔布（考克斯-2的选择性抑制剂），不影响HO-1的表达。用有效诱导HO-1的浓度的AZD 3582预处理内皮细胞也减少了NADPH依赖的氧自由基产生。在AZD 3582从孵育培养基中洗出后，内皮细胞中的抗氧化活性仍然存在。当以低微摩尔浓度外源性加入细胞时。HO-1代谢产物胆红素实际上消除了NADPH依赖性氧化应激。在HO-1抑制剂锡原卟啉-IX（SnPP）的存在下，AZD 3582诱导的自由基形成阻滞被逆转。在人胃粘膜细胞（KATO-III）中获得了类似的结果。我们的研究结果表明HO-1是AZD 3582的新靶点。(c)2005 Elsevier B. V.保留所有权利。
AZD3582 [4-(nitrooxy)-butyl-(2S)-2-(6-methoxy-2-naphthyl)-propanoate] is a COX-inhibiting nitric oxide donator (CINOD). Incubation of human endothelial cells (derived from umbilical cord) with AZD3582 (10-100 mu M) led to increased expression of heme oxygenase (HO)-1 mRNA and protein. Heme oxygenase-1 (HO-1) is a crucial mediator of antioxidant and tissue-protective actions. In contrast, naproxen (a nonselective NSAID) and rofecoxib (a selective inhibitor of COX-2), did not affect HO-1 expression. Pre-treating endothelial cells with AZD3582 at concentrations that were effective at inducing HO-1 also reduced NADPH-dependent production of oxygen radicals. Antioxidant activity in the endothelial cells persisted after AZD3582 had been washed out from the incubation medium. When added exogenously to the cells at low micromolar concentrations. the HO-1 metabolite, bilirubin, virtually abolished NADPH-dependent oxidative stress. AZD3582-induced blockade of free-radical formation was reversed in the presence of the HO-1 inhibitor, tin protoporphyrin-IX (SnPP). Similar results were obtained in human gastric mucosal cells (KATO-III). Our results demonstrate that HO-1 is a novel target of AZD3582. (c) 2005 Elsevier B.V. All rights reserved.