Hematopoietic NF-kappaB1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype.

Abstract

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.

• Authors: Edwin Kanters, Marion J J Gijbels, Ingeborg van der Made, Monique N Vergouwe, Peter Heeringa, Georg Kraal, Marten H Hofker, Menno P J de Winther
• Journal: Blood (Blood) Vol. 103 Issue 3 Pg. 934-40 (Feb 01 2004) ISSN: 0006-4971 [Print] United States
• PMID: 14512319 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Lipoproteins
• Membrane Proteins
• NF-kappa B
• Receptors, Immunologic
• Receptors, LDL
• Receptors, Lipoprotein
• Receptors, Scavenger
• Scarb1 protein, mouse
• Scavenger Receptors, Class A
• Scavenger Receptors, Class B

Topics

• Animals
• Arteriosclerosis (etiology, genetics, pathology, physiopathology)
• Bone Marrow Cells (pathology)
• Cytokines (metabolism)
• Endocytosis
• Female
• Inflammation (etiology, genetics, pathology, physiopathology)
• Lipoproteins (metabolism)
• Macrophage Activation
• Macrophages (immunology, pathology)
• Membrane Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (deficiency, genetics)
• Phenotype
• Radiation Chimera
• Receptors, Immunologic (metabolism)
• Receptors, LDL (deficiency, genetics)
• Receptors, Lipoprotein
• Receptors, Scavenger
• Scavenger Receptors, Class A
• Scavenger Receptors, Class B