STUDY ON THE SIGNIFICANCE OF LOX-1 IN OXIDATIVE STRESS-RELATED BIOLOGICAL RESPONSES

我们已经确定了内皮细胞中表达的氧化LDL受体。在此基础上提出了LOX-1在氧化应激相关病理反应和疾病中的作用。在本研究中，我们采用(1)大鼠球囊动脉损伤模型和(2)LOX-1过表达ApoEKO小鼠来探讨LOX-1在PTCA后内膜增厚和冠状动脉粥样硬化中的作用。(1)充气球囊导管损伤大鼠颈动脉内膜。RT-PCR检测损伤后LOX-1表达的诱导情况。抗LOX-1抗体免疫组织化学表明，LOX-1早期定位于内膜平滑肌细胞，中期定位于内膜平滑肌细胞，晚期定位于再生内皮细胞。抗lox -1抗体治疗可降低内膜增厚、白细胞浸润和氧化应激。(2)分析LOX-1过表达ApoEKO小鼠的心脏，并与ApoEKO小鼠进行比较。与ApoEKO小鼠相比，LOX-1过表达小鼠的氧化LDL沉积、氧化应激、粘附分子表达、巨噬细胞浸润和脂质沉积增加。这些结果提示LOX-1参与了高脂血症下球囊动脉损伤后内膜增厚和脂质沉积的病理过程。在这两种模型中，氧化应激均增加，而LOX-1至少在一定程度上增强了病变中的氧化应激。控制LOX-1活性可能是治疗包括这些疾病在内的氧化应激相关疾病的新方法。

We have identified the oxidized LDL receptor expressed in endothelial cells. After the discovery, roles of LOX-1 in oxidative stress-related pathological responses and diseases were suggested. In the present study, we have employed (1) rat model for balloon arterial injury and (2) LOX-1 overexpressing ApoEKO mice to explore the role of LOX-1 in intimal thickening after PTCA and in coronary atherosclerosis.(1) Intima of rat carotid artery was injured by an inflated balloon catheter. The induction of the expression of LOX-1 was detected immediately after the injury by RT-PCR analyses. Immnohistochemistry with anti-LOX-1 antibody showed LOX-1 was localized in imedial smooth muscle cells n the early phase, in intimal smooth muscle cells in intermediate phase, and in regenerated endothelial cells in the late phase. Treatment with anti-LOX-1 antibody reduced the thickening of intima as well as infiltration of leukocytes and oxidative stress.(2) Heart of the LOX-1 overexpressing ApoEKO mice was analyzed, being compared with ApoEKO mice. Deposition of oxidized LDL, oxidative stress, expression of adhesion molecules, infiltration of macrophages, and lipid deposition were increased in LOX-1 overexpressing mice compared with ApoEKO mice.These results suggest that LOX-1 is involved in the pathology of intimal thickening after balloon arterial injury and lipid deposition under hyper lipidemia. In both models oxidative stress are increased and LOX-1,at least in part, enhances the oxidative stress in the lesion. Manipulating LOX-1 activity might be a novel therapeutic approach for in oxidative stress-related diseases including these diseases.