Genes within the MHC region have a dramatic influence on radiation-enhanced atherosclerosis in mice.

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 μm²/section) and a near 4-fold increase over B6.apoE⁻(/)⁻ mice (40 529±4675 μm²/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 μm²/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 μm²/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.