title: Inflammation in atherosclerosis: lesion formation in LDL receptor-deficient mice with perforin and Lyst(beige) mutations.
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 Lyst(beige) mice (creating beige,LDLr-/- mice) and with perforin-deficient mice (creating Pfp-/-,LDLr-/- mice).
  
  
  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.
authors.affiliation: Scripps Research Institute, Department of Immunology, La Jolla, Calif., USA.
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Schiller
authors.forename: William A
authors.initials: WA
authors.lastname: Boisvert
authors.forename: Linda K
authors.initials: LK
authors.lastname: Curtiss
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism; D001161:Arteriosclerosis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins / Q000235:genetics; D011973:Receptors, LDL / Q000378:metabolism*; D033921:Vesicular Transport Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C491133:Lyst protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; D011973:Receptors, LDL; D033921:Vesicular Transport Proteins; D054353:Perforin