Abstract 3583: The Major Histocompatibility Complex Haplotype is a Major Genetic Determinant of Susceptibility to Radiation induced Atherosclerosis in Mice
BACKGROUND: Although both clinical and experimental animal studies have demonstrated that radiation is an independent risk factor for atherosclerosis, the mechanism is unclear. C3H/HeJ (C3H) mice develop much smaller atherosclerotic lesions than C57BL/6 (B6) mice when deficient in apolipoprotein E (apoE−/−). The two strains differ in the major histocompatibility complex (MHC) haplotype with B6 being H2b and C3H being H2k. C3.SW-H2b/SnJ (C3.SW) is a congenic strain of C3H in which H2k is replaced with H2b.
METHODS AND RESULTS: C3.SW.apoE−/− mice reconstituted with bone marrow from their siblings or B6.apoE−/− mice following lethal irradiation developed significantly larger atherosclerotic lesions than B6.poE−/−recipients reconstituted with identical bone marrow and C3H.apoE−/− recipients reconstituted with bone marrow from siblings. For isogeneic transplantation, C3.SW.apoE−/− mice exhibited a 21-fold increase in atherosclerotic lesion size over C3H.apoE−/− mice (152,800±21,937 vs. 7,060±2,290 μm2/section) and a 3-fold increase over B6.apoE−/− mice (40,529±4,675 μm2/section). B6.apoE−/− mice reconstituted with bone marrow from C3.SW.apoE−/− mice developed a lesion size comparable to those reconstituted with bone marrow from siblings (42,188±5,378 vs. 40,529±4,675 μm2/section). In contrast, C3.SW.apoE−/− mice reconstituted with bone marrow from siblings tended to develop a larger lesion size than those reconstituted with B6 bone marrow (152,800±21,937 vs. 107,000±9,374 μm2/section; P=0.067). Irradiation with a low dose also dramatically increased lesion size in C3.SW.apoE−/− mice (9,795±2,804 vs. 1,550±607 μm2/section; P=0.008).
CONCLUSIONS: These results indicate that the MHC is a major determinant of susceptibility to radiation-induced atherosclerosis and its effect is conveyed partially by acting on bone marrow-derived cells.