Reduction of Isoprostanes and Regression of Advanced Atherosclerosis by Apolipoprotein E





D. Praticó, R.K. Tangirala, G.A. FitzGerald, S.Chun, K.Tsukamoto, C. Maugeais, and D.J. Rader.

Center for Experimental Therapeutics,
University of Pennsylvania
421, Curie Blvd
BRB II/III, room 812
Philadelphia, PA 19104.




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 iPF2alpha-VI and found that
expression of apoE markedly reduced urinary, LDL-associated, and arterial wall iPF2alpha-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.





Key words: Atheroscelrosis, ApolipoproteinE, Lipid peroxidation, Isoprostanes, LDL Receptor-deficient mice.







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