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(Circulation. 2000;101:2510.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Human Serum Paraoxonases (PON1) Q and R Selectively Decrease Lipid Peroxides in Human Coronary and Carotid Atherosclerotic Lesions
PON1 Esterase and Peroxidase-Like Activities
From the Lipid Research Laboratory, Technion Faculty of Medicine, the Rappaport Family Institute for Research in the Medical Sciences (M.A., E.H., M.R.), and the Department of Cardiac Surgery (S.M.) and the Department of Vascular Surgery and Transplantation (A.H.), Rambam Medical Center, Haifa, Israel; the Laboratory of Natural Compounds for Medical Use (J.V., S.M.), Migal, Galilee Technological Center, Kiryat Shmona, Israel; and the Department of Anesthesiology (S.B., D.D.), University of Michigan, Ann Arbor.
Correspondence to Michael Aviram, DSc, The Lipid Research Laboratory, Rambam Medical Center, Haifa 31096, Israel. E-mail aviram{at}tx.technion.ac.il
Background—Human serum paraoxonase (PON1) exists in two polymorphic forms: one that differs in the amino acid at position 192 (glutamine and arginine, Q and R, respectively) and the second one that differs in the amino acid at position 55 (methionine and leucine, M and L, respectively). PON1 protects LDL from oxidation, and during LDL oxidation, PON1 is inactivated.
Methods and Results—The present study compared PON1 isoforms Q and R for their effect on lipid peroxide content in human coronary and carotid lesions. After 24 hours of incubation with PON1Q or PON1R (10 arylesterase units/mL), lipid peroxides content in both coronary and carotid lesion homogenates (0.1 g/mL) was reduced up to 27% and 16%, respectively. The above incubation was associated with inactivation of PON1Q and PON1R by 15% and 45%, respectively. Lesion cholesteryl linoleate hydroperoxides and cholesteryl linoleate hydroxides were hydrolyzed by PON1 to yield linoleic acid hydroperoxides and linoleic acid hydroxides. Furthermore, lesion and pure linoleic acid hydroperoxides were reduced to yield linoleic acid hydroxides. These results thus indicate that PON1 demonstrates esterase-like and peroxidase-like activities. Recombinant PON1 mutants in which the PON1-free sulfhydryl group at cysteine-284 was replaced with either alanine or serine were no longer able to reduce lipid peroxide content in carotid lesions.
Conclusions—We conclude that PON1 may be antiatherogenic because it hydrolyzes lipid peroxides in human atherosclerotic lesions.
Key Words: fatty acids • arteries • carotid arteries • atherosclerosis • lipids • lesion • cholesterol
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