Hematopoietic NF-kappaB1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype.
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-laden macrophages in the vessel wall. One of the major transcription factors in inflammation is nuclear factor kappaB (NF-kappaB), and we have studied its role in the development of atherosclerosis. Bone marrow from mice targeted in the NF-kappaB1 gene encoding for the p50 subunit was used to reconstitute irradiated LDLR(-/-) mice as a model for atherosclerosis. After feeding the mice a high-fat diet, those deficient in NF-kappaB1 had a 41% lower rate of atherosclerosis than control mice, as judged by the sizes of the lesions. Furthermore, in the absence of NF-kappaB1, the lesions were characterized by an inflammatory phenotype, contained increased numbers of small cells, and were almost devoid of normal foam cells. In vitro studies using bone marrow (BM)-derived macrophages showed that macrophages lacking p50 had a prolonged production of tumor necrosis factor (TNF) in response to lipopolysaccharide (LPS), and other cytokines were also affected. Interestingly, the uptake of oxidized low-density lipoprotein (LDL) was greatly reduced in activated p50-deficient macrophages, probably because of a reduction in the expression of scavenger receptor class A. The effects on atherosclerosis might have resulted from the changes in cytokine production and the uptake of modified lipoproteins, making p50 a pivotal regulator of atherogenesis.
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004705:Endocytosis; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008074:Lipoproteins / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D011828:Radiation Chimera; D011971:Receptors, Immunologic / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B
D016207:Cytokines; D008074:Lipoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B