Aldose reductase functions as a detoxification system for lipid peroxidation products in vasculitis
Aldose reductase functions as a detoxification system for lipid peroxidation products in vasculitis
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DOI：
10.1172/jci4711
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发表时间：
1999-04-01
影响因子：
15.9
通讯作者：
Weyand, CM
中科院分区：
文献类型：
--
作者：
Rittner, HL;Hafner, V;Weyand, CM
巨细胞动脉炎（GCA）是一种系统性血管炎，优先影响大型和中型动脉。动脉壁中的炎性浸润诱导管腔闭塞，随后缺血和弹性膜降解，从而形成动脉瘤。为了鉴定与疾病过程相关的途径，使用差异显示-PCR。醛糖还原酶（AR），这是涉及的调节：问题渗透压，被发现在动脉炎病变上调。上调的AR表达仅限于发炎动脉中的组织破坏区域，其中在T细胞、巨噬细胞和平滑肌细胞中检测到。AR的产生与4-羟基壬烯醛（HNE）的存在高度相关，4-羟基壬烯醛是一种有毒的醛和脂质过氧化的下游产物。单核细胞体外暴露于HNE足以诱导AR产生。通过用AR抑制剂Sorbinil和Zopolrestat处理人GCA颞动脉-严重联合免疫缺陷（SCID）小鼠嵌合体，探索AR和HNE的体内关系。抑制AR增加HNE加合物的两倍和动脉壁中的凋亡细胞的数量的三倍。这些数据表明，AR通过防止脂质过氧化损伤具有组织保护功能。我们认为AR是一种氧化防御机制，能够中和脂质过氧化的毒性作用，并在限制活性氧介导的动脉壁损伤中发挥作用。
Giant cell arteritis (GCA) is a systemic vasculitis preferentially affecting large and medium-sized arteries. Inflammatory infiltrates in the arterial wall induce luminal occlusion with subsequent ischemia and degradation of the elastic membranes, allowing aneurysm formation. To identify pathways relevant to the disease process, differential display-PCR was used. The enzyme aldose reductase (AR), which is implicated in the regulation oft:issue osmolarity, was found to be upregulated in the arteritic lesions. Upregulated AR expression was limited to areas of tissue destruction in inflamed arteries, where it was detected in T cells, macrophages, and smooth muscle cells. The production of AR was highly correlated with the presence of 4-hydroxynonenal (HNE), a toxic aldehyde and downstream product of lipid peroxidation. In vitro exposure of mononuclear cells to HNE was sufficient to induce AR production. The in vivo relationship of AR and HNE was explored by treating human GCA temporal artery-severe combined immunodeficiency (SCID) mouse chimeras with the AR inhibitors Sorbinil and Zopolrestat. Inhibition of AR increased HNE adducts twofold and the number of apoptotic cells in the arterial wall threefold. These data demonstrate that AR has a tissue-protective function by preventing damage from lipid peroxidation. We propose that AR is an oxidative defense mechanism able to neutralize the toxic effects of lipid peroxidation and has a role in limiting the arterial wall injury mediated by reactive oxygen species.