Inflammation in atherosclerosis: lesion formation in LDL receptor-deficient mice with perforin and Lyst(beige) mutations.

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 Lyst(beige) 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 Lyst(beige) mutation in LDLr-/- mice has proatherogenic properties that are independent of NK cell-mediated cytolysis and lymphocyte-mediated acquired immunity.