Reduction of Isoprostanes and Regression of Advanced Atherosclerosis by Apolipoprotein E

Abstract

Apolipoprotein E is a multifunctional protein synthesized by hepatocytes and macrophages. Plasma apoE is largely liver-derived and known to regulate lipoprotein metabolism. Macrophage-derived apoE has been shown to reduce the progression of atherosclerosis in mice. We tested the hypothesis that liver-derived apoE could directly induce regression of pre-existing advanced atherosclerotic lesions without reducing plasma cholesterol levels. Aged low density lipoprotein (LDL) receptor-deficient (LDLR ؊/؊ ) mice were fed a westerntype diet for 14 weeks to induce advanced atherosclerotic lesions. One group of mice was sacrificed for evaluation of atherosclerosis at base line, and two other groups were injected with a second generation adenoviruses encoding human apoE3 or a control empty virus. Hepatic apoE gene transfer increased plasma apoE levels by 4-fold at 1 week, and apoE levels remained at least 2-fold higher than controls at 6 weeks. There were no significant changes in plasma total cholesterol levels or lipoprotein composition induced by expression of apoE. The liver-derived human apoE gained access to and was retained in arterial wall. Compared with base-line mice, the control group demonstrated progression of atherosclerosis; in contrast, hepatic apoE expression induced highly significant regression of advanced atherosclerotic lesions. Regression of lesions was accompanied by the loss of macrophage-derived foam cells and a trend toward increase in extracellular matrix of lesions. As an index of in vivo oxidant stress, we quantitated the isoprostane iPF 2␣ -VI and found that expression of apoE markedly reduced urinary, LDL-associated, and arterial wall iPF 2␣ -VI levels. In summary, these results demonstrate that liver-derived apoE directly induced regression of advanced atherosclerosis and has anti-oxidant properties in vivo that may contribute to its anti-atherogenic effects.

Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques

“…Cholesterol levels do not drop in apoE Ϫ/Ϫ recipients (12). Transfer of these lesion-rich aortic arches into WT recipients (C57BL͞6 apoE ϩ/ϩ ) results in an immediate conversion to normal lipid profiles, which in turn promotes lesion regression (12), in agreement with nonsurgical methods that restore normal blood lipid profiles and͞or apoE (23,24). Significant changes in lesion area were observed by or before 2 weeks after surgical transfer (Fig.…”

Apolipoprotein E polymorphism is associated with both number of diseased vessels and extent of coronary artery disease in Czech patients with CAD

“…ApoE is produced by macrophages in diseased arterial wall during its inflammatory reaction, where it helps to carry away cholesterol in locally formed lipoproteins and reduce atherosclerotic plaque 7,8 . This effect can be also mediated by hepatic ApoE, as was proven in mice lacking macrophage-derived ApoE, and is responsible for anti-aterogenic action even without lowering plasma cholesterol levels [9][10][11] . The protein also induce the synthesis of NO in vessel wall 12 and has numerous anti-inflammatory effects 13,14 ApoE is polymorphic, with three isoforms common in general population: E2, E3 and E4.…”

Impaired Secretion of Apolipoprotein E2 from Macrophages

“…Experimental evidence suggests that hepatocyte-derived apoE and macrophage-derived apoE may be either functionally different or operate at different physiologic thresholds (10,17,18,(53)(54)(55)(56)(57)(58)(59)(60). The difference in their conformation suggested in this study may underlie the functional difference between hepatocyte and macrophage apoE.…”