Rittner H L, Hafner V, Klimiuk P A, Szweda L I, Goronzy J J, Weyand C M
Department of Medicine, Division of Rheumatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Clin Invest. 1999 Apr;103(7):1007-13. doi: 10.1172/JCI4711.
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 of tissue 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.
巨细胞动脉炎（GCA）是一种系统性血管炎，主要累及大中型动脉。动脉壁中的炎性浸润导致管腔闭塞，随后出现缺血以及弹性膜降解，进而形成动脉瘤。为了确定与疾病进程相关的途径，采用了差异显示聚合酶链反应（differential display-PCR）。发现参与组织渗透压调节的醛糖还原酶（AR）在动脉炎病变中上调。AR表达上调仅限于炎症动脉中组织破坏的区域，在T细胞、巨噬细胞和平滑肌细胞中均可检测到。AR的产生与4-羟基壬烯醛（HNE）的存在高度相关，HNE是一种有毒醛类，也是脂质过氧化的下游产物。单核细胞在体外暴露于HNE足以诱导AR产生。通过用AR抑制剂索比尼尔（Sorbinil）和唑泊司他（Zopolrestat）治疗人GCA颞动脉-严重联合免疫缺陷（SCID）小鼠嵌合体，探讨了AR与HNE在体内的关系。抑制AR可使HNE加合物增加两倍，动脉壁中凋亡细胞数量增加三倍。这些数据表明，AR通过防止脂质过氧化损伤发挥组织保护功能。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。
