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

我们已经鉴定了氧化型低密度脂蛋白受体在内皮细胞中的表达。在发现后，LOX-1在氧化应激相关的病理反应和疾病中的作用被提出。在本研究中，我们采用(1)大鼠球囊损伤模型和(2)高表达LOX-1的ApoEKO小鼠，以探讨LOX-1在PTCA术后内膜增厚和冠状动脉粥样硬化中的作用。RT-PCR检测LOX-1在损伤后即刻的表达。用抗LOX-1抗体进行免疫组织化学染色显示，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。经抗LOX-1抗体处理后，血管内膜增厚、白细胞浸润和氧化应激反应减少。(2)分析LOX-1高表达ApoEKO小鼠的心脏，并与ApoEKO小鼠进行比较。与ApoEKO小鼠相比，LOX-1高表达小鼠的氧化低密度脂蛋白沉积、氧化应激、黏附分子表达、巨噬细胞浸润和脂质沉积增加，提示LOX-1参与了高脂血症下动脉内膜损伤后内膜增厚和脂质沉积的病理过程。在这两种模型中，氧化应激都增加了，LOX-1至少部分地增强了病变中的氧化应激。操纵LOX-1活性可能是包括这些疾病在内的氧化应激相关疾病的一种新的治疗方法。

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.