Circulation. 2002;106:484-490
Published online before print July 1, 2002, doi: 10.1161/01.CIR.0000023623.87083.4F
Published online before print July 1, 2002, doi: 10.1161/01.CIR.0000023623.87083.4F
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(Circulation. 2002;106:484.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Decreased Atherosclerotic Lesion Formation in Human Serum Paraoxonase Transgenic Mice
From the Department of Medicine (A.T., Y.-R.X., X.-P.W., Y.-S.S., C.P., L.W.C., A.J.L., D.M.S.), the Department of Microbiology, Immunology, and Molecular Genetics (A.T., A.J.L.), and the Department of Human Genetics (A.J.L.), University of California, Los Angeles. A. Tward is now at the University of California, San Francisco.
Correspondence to Dr Diana M. Shih, Division of Cardiology, Department of Medicine, University of California, Los Angeles, 47-123 CHS, UCLA, Los Angeles, CA 90095-1679. E-mail dshih{at}mednet.ucla.edu
Background— Serum paraoxonase (PON1), an enzyme carried on HDL, inhibits LDL oxidation, and in human population studies, low PON1 activity is associated with atherosclerosis. In addition, PON1 knockout mice are more susceptible to lipoprotein oxidation and atherosclerosis. To evaluate whether PON1 protects against atherosclerosis and lipid oxidation in a dose-dependent manner, we generated and studied human PON1 transgenic mice.
Methods and Results— Human PON1 transgenic mice were produced by using bacterial artificial chromosome genomic clones. The mice had 2- to 4-fold increased plasma PON1 levels, but plasma cholesterol levels were unchanged. Atherosclerotic lesions were significantly reduced in the transgenic mice when both dietary and apoE-null mouse models were used. HDL isolated from the transgenic mice also protected against LDL oxidation more effectively.
Conclusions— Our results indicate that PON1 protects against atherosclerosis in a dose-dependent manner and suggest that it may be a potential target for developing therapeutic agents for the treatment of cardiovascular disease.
Key Words: antioxidants • lipoproteins • free radicals • atherosclerosis • genes
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