RESUMEN
BACKGROUND: The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed on multiple cell types implicated in the inflammatory response in atherosclerosis. We sought to determine the role of bone marrow-derived RAGE in different stages of atherosclerotic development in apolipoprotein E-deficient mice (apoE(-/-)). METHODS: Seven- and 23-week-old apoE(-/-) mice (n = 40) were lethally irradiated and given bone marrow from RAGE null (RAGE(-/-)/apoE(-/-)) or RAGE-bearing (RAGE(+/+)/apoE(-/-)) mice to apoE(-/-) mice to generate double knockout bone marrow chimera (RAGE(-/-)/apoE(-/-bmc) and RAGE(+/+)/apoE(-/-bmc)-, respectively). After 16 weeks on a standard chow diet, mice were sacrificed and atherosclerotic lesion formation was evaluated. RESULTS: Plaques in the aortic root of the young mice showed no significant difference in maximum plaque size (217,470 ± 17,480 µm(2) for the RAGE(-/-) /apoE(-/-bmc) mice compared to 244,764 ± 45,840 µm(2)), whereas lesions in the brachiocephalic arteries of the older RAGE(-/-)/apoE(-/-bmc) mice had significantly smaller lesions (94,049 ± 13,0844 µm(2) vs. 145,570 ± 11,488 µm(2), P < 0.05) as well as reduced average necrotic core area (48,600 ± 9220 µm(2) compared to 89,502 ± 10,032 µm(2), P < 0.05) when compared to RAGE(+/+)/apoE(-/-bmc) mice. Reduced plaque size and more stable plaque morphology was associated with significant reduced expression of VCAM-1, ICAM-1 and MCP-1. Accumulation of the RAGE ligand HMGB-1 was also significantly reduced within the lesions of RAGE(-/-)/apoE(-/-bmc) mice. CONCLUSIONS: This study demonstrates that bone marrow-derived RAGE is an important factor in the progression of atherosclerotic plaques.
Asunto(s)
Apolipoproteínas E/deficiencia , Aterosclerosis/prevención & control , Trasplante de Médula Ósea , Productos Finales de Glicación Avanzada/metabolismo , Receptores Inmunológicos/fisiología , Animales , Aterosclerosis/metabolismo , Médula Ósea/inmunología , Quimiocina CCL2/metabolismo , Femenino , Proteína HMGB1/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor para Productos Finales de Glicación Avanzada , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
Atherosclerosis is a progressive inflammatory disease of the medium to large arteries that is the largest contributor to cardiovascular disease. B-cell subsets have been shown in animal models of atherosclerosis to have both atherogenic and atheroprotective properties. In this review, we highlight the research that developed our understanding of the role of B cells in atherosclerosis both in humans and mice. From this we discuss the potential clinical impact B cells could have both as diagnostic biomarkers and as targets for immunotherapy. Finally, we recognize the inherent difficulty in translating findings from animal models into humans given the differences in both cardiovascular disease and the immune system between mice and humans, making the case for greater efforts at addressing the role of B cells in human atherosclerosis.
Asunto(s)
Aterosclerosis , Subgrupos de Linfocitos B , Animales , Aterosclerosis/inmunología , Aterosclerosis/patología , Aterosclerosis/terapia , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/patología , Biomarcadores , Humanos , RatonesRESUMEN
AIMS: Early growth response gene-1 (Egr-1) regulates the expression of genes important to cardiovascular disease. Within atherosclerotic lesions, Egr-1 is expressed in smooth muscle cells, endothelial cells, and macrophages. Since macrophages play a pivotal role in atherosclerotic lesion initiation and progression, this study investigated the effects of Egr-1 deficiency within bone marrow-derived cells on the development of atherosclerosis in a hyperlipidaemic mouse model. METHODS AND RESULTS: Bone marrow from Egr-1-deficient mice and wild-type controls was transplanted into lethally irradiated LDL receptor null mice. After 26 weeks on a high fat diet, atherosclerotic lesion size within the aortic sinus of recipients was evaluated. Mice receiving Egr-1-deficient bone marrow had significantly decreased lesion size compared with controls. Lesions of these mice contained fewer macrophages and had reduced expression of vascular cell adhesion molecule-1 (VCAM-1), tissue factor, as well as transforming growth factor receptor type II, which are target genes of Egr-1. These results were validated by in vitro analysis of Egr-1-deficient peritoneal macrophages which, after lipopolysaccharide stimulation, had decreased VCAM-1 and tissue factor mRNA expression compared with wild-type controls. CONCLUSION: This study demonstrates that bone marrow-derived Egr-1 promotes macrophage accumulation, atherosclerotic lesion development, and lesion complexity.