Abstract 020: Regression of Atherosclerosis Through Manipulation of Vascular Macrophages; a Novel Gene-therapy Approach

Abstract

Aggressive lipid lowering halts atherosclerotic plaque progression but does not lead to bulk plaque regression in humans. We have previously reported that gene transfection of the HDL protein apoAI into macrophages (MΦ-apoAI) decrease the rate of plaque development in atherosclerosis-prone mice. In this study, we hypothesized that MΦ-apoAI can promote regression of atherosclerosis synergistically with lipid-lowering. Atherogenic mice (LDLR -/- and LDLR -/- /MΦ-apoAI) were fed a high-fat diet to promote stage II/III atherosclerotic lesions (as baseline comparator), and then switched to an extreme lipid-lowering intervention (chow with MTTP inhibitor). After 3 weeks on the lipid-lowering diet, both groups showed reduced systemic and lesion inflammation, and reduced macrophage content on histology when compared to baseline. Upon lipid-lowering, vascular ultrasound showed that LDLR -/- /MΦ-apoAI mice has 21% improvement in aortic pulse transit time, and a 37.1% improvement in instantaneous aortic compliance (a surrogate marker for arterial elastic modulus), compared to LDLR -/- mice. Histologic evidence showed that LDLR -/- /MΦ-apoAI mice on lipid-lowering diet also had reduced lesion size (-24%), reduced macrophage content (-27.5%), increased M2/M1 ratio (+51%) and reduced necrotic core area (-28.6%), compared to LDLR -/- mice. Using transplantation of bone marrow cells from MΦ-apoAI mice into recipient mice with established lesions, we show that newly recruited cells are not major contributors to the regression afforded by MΦ-apoAI. Thus, to study the kinetics of pre-existing cells in the lesion during regression, we developed a contrast ultrasound-mediated gene delivery system to tag and trace lesion cells in LDLR -/- mice, which revealed that lesion macrophages expressing apoAI specifically migrate to mediastinal LN in a CCR7-dependent manner during regression. Expression of apoAI in pre-existing lesion macrophages, promotes regression of atherosclerosis beyond lipid-lowering alone, and increases CCR7-dependent egress of macrophages to adjacent lymph nodes. Ultrasound-mediated gene delivery can be a useful device to study the kinetics of cell in the artery wall and also represent a novel approach with application to human therapy.