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 western-type 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 alpha)-VI and found that expression of apoE markedly reduced urinary, LDL-associated, and arterial wall iPF(2 alpha)-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.

• Authors: R K Tangirala, D Praticó, G A FitzGerald, S Chun, K Tsukamoto, C Maugeais, D C Usher, E Puré, D J Rader
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 1 Pg. 261-6 (Jan 05 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11024044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antioxidants
• Apolipoproteins E
• Receptors, LDL
• Cholesterol
• Dinoprost

Topics

• Adenoviridae (genetics)
• Animals
• Antioxidants (metabolism, therapeutic use)
• Aorta (metabolism, pathology)
• Apolipoproteins E (blood, genetics, metabolism, therapeutic use)
• Arteriosclerosis (drug therapy, metabolism, pathology)
• Cholesterol (blood)
• Diet, Atherogenic
• Dinoprost (analogs & derivatives, metabolism, urine)
• Disease Progression
• Endothelium, Vascular (metabolism, pathology)
• Extracellular Matrix (metabolism)
• Gene Transfer Techniques
• Humans
• Liver (metabolism)
• Mice
• Mice, Knockout
• Oxidative Stress
• Receptors, LDL (deficiency, genetics, physiology)