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.
Ishigaki
Yasushi
Y
Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
Katagiri
Hideki
H
Gao
Junhong
J
Yamada
Tetsuya
T
Imai
Junta
J
Uno
Kenji
K
Hasegawa
Yutaka
Y
Kaneko
Keizo
K
Ogihara
Takehide
T
Ishihara
Hisamitsu
H
Sato
Yuko
Y
Takikawa
Kenji
K
Nishimichi
Norihisa
N
Matsuda
Haruo
H
Sawamura
Tatsuya
T
Oka
Yoshitomo
Y
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