Retrovirus-mediated Expression of Apolipoprotein A-I in the Macrophage Protects against Atherosclerosis in Vivo

Abstract

We have previously reported that the lack of apolipoprotein (apo) E expression by macrophages promotes foam cell formation in vivo. Because transgenic mice overexpressing human apoA-I from the liver (h-apoA-I TgN) are protected from the atherogenesis induced by apoE deficiency, we hypothesized that the presence of apoA-I in the vessel wall could reduce the negative effect of apoE deficiency on lesion growth. To address this issue, we used both retroviral transduction and transgenic approaches to produce in vivo systems where apoA-I is expressed from macrophages. In the retroviral transduction study, apoA-I-deficient (apoA-I ؊/؊ ) mice reconstituted with apoE-deficient (apoE ؊/؊ ) bone marrow cells that were infected with a retroviral vector expressing human apoA-I (MFG-HAI) had 95% lower atherosclerotic lesion area than that of recipients of apoE ؊/؊ bone marrow cells infected with the parental virus (MFG). To determine whether the protective effect of locally produced apoA-I was due to the lack of systemic apoA-I, we conducted a different experiment using h-apoA-I TgN mice as recipients of apoE ؊/؊ bone marrow with or without human apoA-I (driven by a macrophage-specific transgene defined as m-AI). Aortic lesion area in apoE ؊/؊ /m-AI 3 h-apoA-I TgN mice was decreased by 85% compared with apoE ؊/؊ 3 h-apoA-I TgN mice. These data demonstrate that expression of apoA-I from macrophages protects against atherogenesis without affecting plasma apoA-I and high density lipoprotein cholesterol levels.

Macrophages, inflammation, and atherosclerosis

“…29 ApoE may be the primary driver of cholesterol efflux in macrophages through a pathway independent from ABC-A1. However, our recent observations that the transgenic or retrovirus-based expression of apoAI from the macrophage corrects the increased atherosclerosis induced by deletion of apoE from the same cell type 22,23 support the notion that apoE-induced cholesterol efflux is quantitatively in the same range as that obtainable through ABCA1-dependent (apoAI-mediated) events. It has been determined that both apoE and ABCA1 genes are regulated by the PPARg-LXR axis, and the macrophage-specific deletion of PPARg reduces levels of apoE and ABCA1 mRNAs, and drastically decreases basal cholesterol efflux.…”

“…20 Furthermore, the removal of macrophage apoE increases lesion size in C57BL/6 mice on a high-fat diet, 21 as well as in apoAI À/À , apoAI overexpressing, and LDL-R À/À mice. 22,23 Expression of very low levels of murine or human apoE from retrovirus-transduced macrophages in apoE-null mice results in decreased lesion area during the early stages of atherosclerosis. 24 This effect is not observed if the human apoE is defective in LDLR-(apoE2) or proteoglycan-binding ability (apoEcys142), thus suggesting that proximity to the plasma membrane is essential for the biologic action of apoE in the vessel wall.…”

Macrophage apoAI protects against dyslipidemia-induced dermatitis and atherosclerosis without affecting HDL

“…However, skin-draining LNs of apoAI recipient mice showed a signifi cant re- affects atherosclerosis both by reducing serum lipid levels ( 46,47 ) and by exerting local effects on the forming atheroma ( 48 ). In contrast, transgenic expression of apoAI from macrophages has been shown to reduce atherogenesis in mice exclusively via local effects and without altering serum lipid levels ( 12,13,17 ). In this study, LDLR…”

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

“…In addition, apo E interacts with ABCA1 to extract cellular cholesterol out of the cell, and drives the formation of larger HDL-sized particles from macrophage foam cells (143,144 ). Because atheromatous plaques are only partially permeable to plasma solutes, such as apo AI, but rich in locally secreted proteins, such as apo E, arterial macrophages may represent cells in a unique microenvironment in which cholesterol efflux is directed more toward apo E-containing particles rather than toward classical apo AI-containing particles (145,146 ).…”