Objective-Mice null for both apolipoprotein (apo)E and scavenger receptor (SR)-BI (DKO) develop severe hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarction, and premature death. The current study examines the ability of macrophage apoE to improve the dyslipidemia, reduce atherosclerosis, and rescue the lethal phenotype of DKO mice. Methods and Results-Initially, bone marrow transplantation (BMT) was unsuccessful, because the DKO mice died from a rapidly fatal anemia 3

more »

... to 5 days after lethal irradiation. Therefore, probucol was used to rescue the DKO mice during BMT and was discontinued 2-weeks after BMT, allowing successful reconstitution with donor marrow. Twelve male apoE Ϫ/Ϫ SR-BI Ϫ/Ϫ mice fed 0.5% probucol in a chow diet were lethally irradiated and transplanted with either wild-type (WT) or DKO bone marrow. Two-weeks after BMT, apoE was detected in serum in WT3 DKO mice, and mean serum cholesterol levels were reduced by 70% versus DKO3 DKO mice. Lipoprotein profiles and HDL subpopulations in WT3 DKO mice were similar to apoE ϩ/ϩ SR-BI Ϫ/Ϫ 3 DKO mice and resembled those of SR-BI Ϫ/Ϫ mice. In WT3 DKO mice, aortic atherosclerosis was reduced by 88% to 90% versus DKO3 DKO mice. Furthermore, the DKO3 DKO mice died Ϸ8 weeks after BMT, whereas WT3 DKO mice exhibited a life span Ͼ40 weeks after BMT. Conclusions-Macrophage apoE is able to rescue the lethal phenotype of apoE Ϫ/Ϫ SR-BI Ϫ/Ϫ mice by improving the dyslipidemia and dramatically reducing atherosclerotic lesion development. (Arterioscler Thromb Vasc Biol. 2006;26: 150-156.)