Published Online
on June 16, 2008

A more recent version of this article appeared on July 1, 2008

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Submitted on October 9, 2007
Accepted on April 18, 2008

Impact of Plasma Oxidized Low-Density Lipoprotein Removal on Atherosclerosis

Yasushi Ishigaki MD, PhD, Hideki Katagiri MD, PhD^*, Junhong Gao MD, PhD, Tetsuya Yamada MD, PhD, Junta Imai MD, PhD, Kenji Uno MD, PhD, Yutaka Hasegawa MD, PhD, Keizo Kaneko MD, Takehide Ogihara MD, PhD, Hisamitsu Ishihara MD, PhD, Yuko Sato PhD, Kenji Takikawa BA, Norihisa Nishimichi PhD, Haruo Matsuda DVM, PhD, Tatsuya Sawamura MD, PhD, and Yoshitomo Oka MD, PhD

From the Division of Molecular Metabolism and Diabetes (Y.I., J.G., T.Y., J.I., Y.H., K.K., H.I., Y.O.) and Division of Advanced Therapeutics for Metabolic Diseases, Center for Translational and Advanced Animal Research (H.K., K.U., K.K., T.O.), Tohoku University Graduate School of Medicine, Sendai; Department of Vascular Physiology, National Cardiovascular Center Research Institute, Osaka (Y.S., T.S.); and Laboratory of Immunobiology, Department of Molecular and Applied Biosciences, Graduate School of Biosphere Science, Hiroshima University, Hiroshima (K.T., N.N., H.M.), Japan.

^* To whom correspondence should be addressed. E-mail: katagiri{at}mail.tains.tohoku.ac.jp.

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.

Methods and 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.

Key words: atherosclerosis • lipoproteins • oxidative stress • oxidized low-density lipoprotein

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