Abstract 375: Inducible ApoE Gene Repair in HypoE Mice Deficient in the LDL Receptor Promotes Atheroma Stabilization with a Human-like Lipoprotein Profile

Abstract

Studies of atherosclerosis regression often investigated the process in the setting of a plasma lipoprotein profile dominated by HDL. To better model humans subjected to lipid lowering therapy, we sought to study atherosclerosis regression in mice that displayed moderately elevated plasma LDL. To achieve this goal, we made use of our HypoE mice deficient in the LDL receptor (Apoeh/hLdlr−/−Mx1-Cre mice) that develop spontaneous hyperlipidemia and atherosclerosis on a chow diet due to reduced apoE expression levels. Twenty-week old mice were studied before and after inducible Cre-mediated Apoe gene repair. After 1 week, induced mice displayed a 2-fold reduction in plasma cholesterol and triglyceride to 337±27 mg/dl and 182±15 mg/dl respectively. This led to a rise in plasma HDL and apoAI levels as well as large apoE-rich HDL. The resulting non-HDL:HDL cholesterol ratio decreased from 7 (87%:13%) to 1.5 (60%:40%). These plasma lipid changes occurred in mice that were fed a chow diet throughout the study, allowing us to study atheroma remodeling in the absence of potential confounding effects due to feeding or withdrawal of a high fat diet. Normalizing Apoe gene expression halted atherosclerosis progression and promoted lesional macrophage loss and collagen accumulation for up to 8 weeks. However, this did not lead to a significant loss of arterial lipid. Concomitantly, blood Ly-6Chi monocytes were decreased by 2-fold but lesional macrophage apoptosis was unchanged. The expression of several genes involved in extra-cellular matrix remodeling and cell migration were changed in lesional macrophages isolated by laser capture microdissection 1 week after Apoe gene repair. However, mRNA levels of numerous genes involved in cholesterol efflux were not significantly changed at this time point. Collectively, our data demonstrate that an abrupt reduction of hyperlipidemia to a normal human-like ratio of plasma non-HDL:HDL cholesterol, can promote lesion stabilization in the absence of arterial lipid loss. Future studies of circulating monocytes and lesional macrophages in our model will seek to uncover genetic pathways that can be manipulated therapeutically to promote atherosclerosis stabilization and regression in the setting of moderately elevated LDL.