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J. Biol. Chem., Vol. 279, Issue 43, 45085-45092, October 22, 2004

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Endothelial Lipase Modulates Susceptibility to Atherosclerosis in Apolipoprotein-E-deficient Mice^*

Tatsuro Ishida, Sungshin Y. Choi¶, Ramendra K. Kundu, Josh Spin, Tomoya Yamashita, Ken-ichi Hirata, Yoko Kojima, Mitsuhiro Yokoyama, Allen D. Cooper¶, and Thomas Quertermous||

From the Donald W. Reynolds Cardiovascular Clinical Research Center, Divisions of Cardiovascular Medicine and Gastroenterology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, the Division of Cardiovascular and Respiratory Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan, and the ^¶Research Institute, Palo Alto Medical Foundation, Palo Alto, California 94301

Endothelial lipase (EL) expression correlates inversely with circulating high density lipoprotein (HDL) cholesterol levels in genetic mouse models, and human genetic variation in this locus has been linked to differences in HDL cholesterol levels. These data suggest a role for EL in the development of atherosclerotic vascular disease. To investigate this possibility, LIPG-null alleles were bred onto the apoE knockout background, and the homozygous double knockout animals were characterized. Both apoE knockout and double knockout mice had low HDL cholesterol levels when compared with wild-type mice, but the HDL cholesterol levels of the double knockout mice were higher than those of apoE knockout mice. Atherogenic very low density lipoprotein and intermediate density lipoprotein/low density lipoprotein cholesterol levels of the double knockout mice were also greater than those of the apoE knockout animals. Despite this lipid profile, there was a significant 70% decrease in atherosclerotic disease area in double knockout mice on a regular diet. Immunohistochemistry and protein blot studies revealed increased EL expression in the atherosclerotic aortas of the apoE knockout animals. An observed decrease in macrophage content in vessels lacking EL correlated with ex vivo vascular monocyte adhesion assays, suggesting that this protein can modulate monocyte adhesion and infiltration into diseased tissues. These data suggest that EL may have indirect atherogenic actions in vivo through its effect on circulating HDL cholesterol and direct atherogenic actions through vascular wall processes such as monocyte recruitment and cholesterol uptake.

Received for publication, June 8, 2004 , and in revised form, July 16, 2004.

^* This work was supported by the Donald W. Reynolds Cardiovascular Clinical Research Center at Stanford University, National Institutes of Health Grant DK38318 (to A. D. C.), the Stanford University Digestive Diseases Center Grant DK38107, the American Heart Association (to S. Y. C.), the 21st Century COE Program from Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Study Group of Molecular Cardiology (to T. I). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr., Falk CVRC, Stanford, CA 94305. Tel.: 650-723-5013; Fax: 650-725-2178; E-mail: tomq1{at}stanford.edu.

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