Abstract 5812: A Novel Role of Insulin Degrading Enzyme (IDE) in Atherosclerosis: Studies Using IDE −/− Bone Marrow-Derived Cells Show Increased Lesion Development in a Bone Marrow Transplant LDL Receptor −/− Mouse Model

Abstract

Insulin degrading enzyme (IDE) hypofunction has been shown to promote Alzheimer’s disease as well as type II diabetes in humans and animal models, but it is unknown if IDE has a role in atherosclerosis. The scavenger receptor-A (SRA) plays a key role in foam cell formation as well as fatty streak development. Using affinity chromatography we previously identified a novel interaction between SRA and IDE from J774 cytosolic lysate. Utilizing a bone marrow transplant model, we tested the hypothesis that IDE knockout in bone marrow derived cells would increase atherosclerotic lesion severity in C57BL-6 mice on an LDLr −/− background fed a high fat diet. At 8 weeks of age, male and female LDLr −/− recipient mice underwent γ -irradiation to eliminate endogenous bone marrow. Recipient mice were repopulated with bone marrow from either wild type or IDE −/− , aged matched donor mice. Following 6 weeks of recovery, recipient mice were placed on a high fat diet (21% fat & 0.15% cholesterol) for 8 weeks to generate an atherosclerotic phenotype. In vivo results showed a significant increase in aortic arch lesion area in male mice (6-fold increased lesion area in IDE −/− (n=8) vs. WT (n=12), p<0.001) and a corresponding increase in aortic root lesion size (2.5-fold increased lesion area in IDE −/− (n=12) vs. WT (n=12), p<0.05). Total serum cholesterol was increased in male recipients repopulated with IDE −/− vs. WT (p<0.001). In vitro mechanistic studies using IDE −/− bone marrow-derived macrophages have revealed differences in adhesion (3.2-fold increase in non-adherent cells from IDE −/− mice vs. WT, p<0.05) as well as a difference in uptake and esterification of tritium-labeled oleate ( 3 H) into cholesterol ester (2-fold increase in acLDL incorporation of 3 H oleate in IDE −/− cells vs. WT cells). This suggests IDE plays a key role in macrophage function and foam cell formation during lesion development. To conclude, IDE −/− bone marrow-derived cells resulted in significantly greater lesion development when transplanted into LDLr −/− male mice. These results indicate a prominent role for IDE in atherosclerotic lesion formation and suggest that IDE may provide a novel target for therapeutic intervention.