Inflammation in Atherosclerosis: Lesion Formation in LDL Receptor–Deficient Mice With Perforin and Lystbeige Mutations

N. K. Schiller, W. Boisvert, L. Curtiss
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引用次数: 62

Abstract

Objective—Natural killer (NK) cells have been identified in human vascular pathologies. In this study, we identified NK cells in aortic root atherosclerotic lesions of low density lipoprotein (LDL) receptor–deficient (LDLr−/−) mice. To characterize the role of NK cell–mediated cytolysis in atherosclerosis, we generated C57Bl/6 double-mutant mice by crossing LDLr−/− mice with NK cell–defective Lystbeige mice (creating beige,LDLr−/− mice) and with perforin-deficient mice (creating Pfp−/−,LDLr−/− mice). Methods and Results—Male mice (8 to 10 weeks old) were fed a high-fat diet to induce atherosclerosis. Compared with LDLr−/− mice, beige,LDLr−/− mice had impaired NK cell cytolytic activity and significantly increased atherosclerosis (P <0.05). Pfp−/−,LDLr−/− mice had impaired NK cell cytolytic activity, yet they had lesions that were similar to those of control mice. This suggested that NK cell cytolysis did not play a significant role in atherosclerosis and that the exacerbated atherosclerosis of the beige,LDLr−/− mouse was independent of impaired NK cell cytolytic activity. Therefore, we investigated the role of T and B lymphocytes in atherosclerosis of beige mice by crossing them with recombinase activator gene 1–deficient LDLr−/− mice (Rag1−/−,LDLr−/− mice), thus creating beige,Rag1−/−, LDLr−/− mice. As in the double-mutant study, beige,Rag1−/−,LDLr−/− mice had significantly increased lesions compared with Rag1−/−,LDLr−/− control mice. Conclusions—Therefore, the Lystbeige mutation in LDLr−/− mice has proatherogenic properties that are independent of NK cell–mediated cytolysis and lymphocyte-mediated acquired immunity.
动脉粥样硬化中的炎症:低密度脂蛋白受体缺陷小鼠穿孔素和溶米色突变的病变形成
目的:自然杀伤(NK)细胞在人体血管病变中已被发现。在这项研究中,我们在低密度脂蛋白(LDL)受体缺陷(LDLr−/−)小鼠的主动脉根部动脉粥样硬化病变中鉴定了NK细胞。为了表征NK细胞介导的细胞溶解在动脉粥样硬化中的作用,我们将LDLr - / -小鼠与NK细胞缺陷的Lystbeige小鼠(产生米色,LDLr - / -小鼠)和穿孔蛋白缺陷小鼠(产生Pfp - / -,LDLr - / -小鼠)杂交,产生C57Bl/6双突变小鼠。方法与结果:采用高脂饲料诱导8 ~ 10周龄雄性小鼠动脉粥样硬化。与LDLr - / -小鼠相比,米色、LDLr - / -小鼠NK细胞溶解活性受损,动脉粥样硬化显著增加(P <0.05)。Pfp−/−、LDLr−/−小鼠的NK细胞溶解活性受损,但其病变与对照小鼠相似。这表明NK细胞的细胞溶解在动脉粥样硬化中没有显著作用,米色、LDLr - / -小鼠动脉粥样硬化的加剧与NK细胞的细胞溶解活性受损无关。因此,我们研究了T淋巴细胞和B淋巴细胞在米色小鼠动脉粥样硬化中的作用,将它们与重组酶激活基因1缺失的LDLr−/−小鼠(Rag1−/−,LDLr−/−小鼠)杂交,从而产生米色,Rag1−/−,LDLr−/−小鼠。在双突变研究中,与Rag1−/−、LDLr−/−对照小鼠相比,米色、Rag1−/−、LDLr−/−小鼠的病变明显增加。因此,LDLr - / -小鼠的Lystbeige突变具有不依赖NK细胞介导的细胞溶解和淋巴细胞介导的获得性免疫的致动脉粥样硬化特性。
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