Genes Within the MHC Region Have a Dramatic Influence on Radiation-Enhanced Atherosclerosis in Mice

Abstract

Background— C3H/HeJ (C3H) mice develop much smaller atherosclerotic lesions than C57BL/6 (B6) mice when deficient in apolipoprotein E (apoE −/− ) or fed an atherogenic diet. The 2 strains differ in H2 haplotypes, with B6 having H2 b and C3H having H2 k . C3.SW-H2 b /SnJ (C3.SW) is a congenic strain of C3H/HeJ in which H2 k is replaced with H2 b . Methods and Results— We performed bone marrow transplantation and found that atherosclerosis-resistant C3.SW.apoE −/− mice reconstituted with bone marrow from either C3.SW.apoE −/− or B6.apoE −/− mice after lethal irradiation had significantly larger atherosclerotic lesions than B6.apoE −/− mice receiving identical treatments and much larger lesions than C3H.apoE −/− mice reconstituted with syngeneic bone marrow. For syngeneic transplantation, C3.SW.apoE −/− mice exhibited a 21-fold increase in lesion size over C3H.apoE −/− mice (152 800±21 937 versus 7060±2290 μm 2 /section) and a near 4-fold increase over B6.apoE −/− mice (40 529±4675 μm 2 /section). C3.SW.apoE −/− mice reconstituted with syngeneic marrow exhibited enhanced lesion formation relative to those reconstituted with B6 marrow (152 800±21 937 versus 107 000±9374 μm 2 /section; P =0.067). Sublethal irradiation led to a 6-fold increase of lesion size in C3.SW.apoE −/− mice (9795±2804 versus 1550±607 μm 2 /section; P =0.008). Wild-type C3.SW mice reconstituted with apoE +/+ or apoE −/− bone marrow had significantly larger atherosclerotic lesions than C3H mice receiving identical treatments on an atherogenic diet. Conclusions— These results indicate that gene(s) within the H2 region have a dramatic impact on radiation-enhanced atherosclerosis, and their effect is conveyed partially through bone marrow–derived cells.