Reactive oxygen species attenuate nitric-oxide-mediated hypoxia-inducible factor-1α stabilization
Reactive oxygen species attenuate nitric-oxide-mediated hypoxia-inducible factor-1α stabilization
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DOI：
10.1016/j.freeradbiomed.2005.12.012
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发表时间：
2006-04-15
影响因子：
7.4
通讯作者：
Brüne, B
中科院分区：
文献类型：
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作者：
Köhl, R;Zhou, J;Brüne, B
组织缺氧/缺血是主要的病理生理决定因素。氧可用性降低的条件引起缺氧诱导因子-1（HIF-1）的积累和活化。最近的报道表明HIF-1在炎症事件中起着至关重要的作用。炎症介质一氧化氮（NO）和活性氧（ROS）对缺氧反应的调节被认为具有病理生理学意义。据报道，HTF-1 α的缺氧稳定性可以被NO拮抗，这是由于其减弱线粒体电子传递的能力。ROS的形成可能有助于这种效应。由于从几项研究中出现了相互矛盾的结果，表明在缺氧期间ROS产生减少或增加，我们使用了通过使用氧化还原循环剂2，3-二甲氧基-1，4-萘醌（DMNQ）模拟缺氧细胞内ROS变化的实验，该氧化还原循环剂在细胞内产生超氧化物。用DMNQ处理A549、HEK 293、HepG 2和COS细胞导致与HIF-1 α积累相关的ROS浓度依赖性升高。通过使用HIF-1 α-von Hippel-Lindau肿瘤抑制蛋白结合试验，我们发现DMNQ产生的ROS损害脯氨酰羟化酶活性。当HIF-1 α被NO稳定时，低浓度的DMNQ（< 1 μ M）显示无作用，1至40 μ M的中间浓度的DMNQ减弱HIF-1 α的积累，并且较高浓度的DMNQ促进HIF-1 α的稳定性。活性氧对NO诱导的HIF-1 α稳定性调节的减弱是由活性蛋白酶体降解途径介导的。总之，我们提出，清除NO的ROS，反之亦然衰减HIF-1 α积累的浓度依赖性方式。这对于充分阐明炎症条件下HIF-1 α的调节是重要的。(c)2005年爱思唯尔公司All rights reserved.
Tissue hypoxia/ischemia are major pathophysiological determinants. Conditions of decreased oxygen availability provoke accumulation and activation of hypoxia-inducible factor-1 (HIF-1). Recent reports demonstrate a crucial role of HIF-1 for inflammatory events. Regulation of hypoxic responses by the inflammatory mediators nitric oxide (NO) and reactive oxygen species (ROS) is believed to be of pathophysiolgical relevance. It is reported that hypoxic stabilization of HTF-1 alpha can be antagonized by NO due to its ability to attenuate mitochondrial electron transport. Likely, the formation of ROS could contribute to this effect. As conflicting results emerged from several studies showing either decreased or increased ROS production during hypoxia, we used experiments mimicking hypoxic intracellular ROS changes by using the redox cycling agent 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), which generates superoxide inside cells. Treatment of A549, HEK293, HepG2, and COS cells with DMNQ resulted in a concentration-dependent raise in ROS which correlated with HIF-1 alpha accumulation. By using a HIF-1 alpha-von Hippel-Lindau tumor suppressor protein binding assay, we show that ROS produced by DMNQ impaired prolyl hydroxylase activity. When HIF-1 alpha is stabilized by NO, low concentrations of DMNQ (< 1 mu M) revealed no effect, intermediate concentrations of 1 to 40 mu M DMNQ attenuated HIF-1 alpha accumulation and higher concentrations of DMNQ promoted HIF-1 alpha stability. Attenuation of NO-induced HIF-1 alpha stability regulation by ROS was mediated by an active proteasomal degradation pathway. In conclusion, we propose that scavenging of NO by ROS and vice versa attenuate HIF-1 alpha accumulation in a concentration-dependent manner. This is important to fully elucidate HIF-1 alpha regulation under inflammatory conditions. (c) 2005 Elsevier Inc. All rights reserved.