Reduction of isoprostanes and regression of advanced atherosclerosis by apolipoprotein E.
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.
Tangirala
R K
RK
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Praticó
D
D
FitzGerald
G A
GA
Chun
S
S
Tsukamoto
K
K
Maugeais
C
C
Usher
D C
DC
Puré
E
E
Rader
D J
DJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000652:urine; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D000975:Antioxidants; D001057:Apolipoproteins E; D011973:Receptors, LDL; D002784:Cholesterol; D015237:Dinoprost