Impact of plasma oxidized low-density lipoprotein removal on atherosclerosis.
BACKGROUND
Several clinical studies of statin therapy have demonstrated that lowering low-density lipoprotein (LDL) cholesterol prevents atherosclerotic progression and decreases cardiovascular mortality. In addition, oxidized LDL (oxLDL) is suggested to play roles in the formation and progression of atherosclerosis. However, whether lowering oxLDL alone, rather than total LDL, affects atherogenesis remains unclear.


RESULTS
To clarify the atherogenic impact of oxLDL, lectin-like oxLDL receptor 1 (LOX-1), an oxLDL receptor, was expressed ectopically in the liver with adenovirus administration in apolipoprotein E-deficient mice at 46 weeks of age. Hepatic LOX-1 expression enhanced hepatic oxLDL uptake, indicating functional expression of LOX-1 in the liver. Although plasma total cholesterol, triglyceride, and LDL cholesterol levels were unaffected, plasma oxLDL was markedly and transiently decreased in LOX-1 mice. In controls, atherosclerotic lesions, detected by Oil Red O staining, were markedly increased (by 38%) during the 4-week period after adenoviral administration. In contrast, atherosclerotic progression was almost completely inhibited by hepatic LOX-1 expression. In addition, plasma monocyte chemotactic protein-1 and lipid peroxide levels were decreased, whereas adiponectin was increased, suggesting decreased systemic oxidative stress. Thus, LOX1 expressed in the livers of apolipoprotein E-deficient mice transiently removes oxLDL from circulating blood and possibly decreases systemic oxidative stress, resulting in complete prevention of atherosclerotic progression despite the persistence of severe LDL hypercholesterolemia and hypertriglyceridemia.


CONCLUSIONS
OxLDL has a major atherogenic impact, and oxLDL removal is a promising therapeutic strategy against atherosclerosis.
Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
Yasushi
Y
Ishigaki
Hideki
H
Katagiri
Junhong
J
Gao
Tetsuya
T
Yamada
Junta
J
Imai
Kenji
K
Uno
Yutaka
Y
Hasegawa
Keizo
K
Kaneko
Takehide
T
Ogihara
Hisamitsu
H
Ishihara
Yuko
Y
Sato
Kenji
K
Takikawa
Norihisa
N
Nishimichi
Haruo
H
Matsuda
Tatsuya
T
Sawamura
Yoshitomo
Y
Oka
D000256:Adenoviridae / Q000235:genetics; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D008054:Lipid Peroxides / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D051131:Receptors, Oxidized LDL / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*
D052242:Adiponectin; D001057:Apolipoproteins E; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; C495138:Olr1 protein, mouse; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein