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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1368.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Adenovirus-Mediated Expression of Human Paraoxonase 3 Protects Against the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice

Carey J. Ng; Noam Bourquard; Susan Y. Hama; Diana Shih; Victor R. Grijalva; Mohamad Navab; Alan M. Fogelman; Srinivasa T. Reddy

From the Atherosclerosis Research Unit, Department of Medicine (C.J.N., N.B., S.Y.H., D.S., V.R.G., M.N., A.M.G., S.T.R.), and the Department of Molecular and Medical Pharmacology (N.B., S.T.R.), David Geffen School of Medicine at UCLA, Los Angeles, Calif.

Correspondence to Srinivasa T. Reddy, PhD, BH 307 CHS, Division of Cardiology, Department of Medicine, 10833 Le Conte Ave, Los Angeles, CA 90095. E-mail sreddy{at}mednet.ucla.edu

Objective— We have previously reported that human paraoxonase 3 (PON3) is an HDL-associated protein capable of preventing LDL oxidation in vitro. The objective of the present study was to determine whether elevated levels of human PON3 in mice could protect against the progression of atherosclerosis in vivo.

Methods and Results— Twenty-six week-old apolipoprotein E–deficient mice were injected with 3x10¹¹particles of adenovirus expressing either GFP alone (AdGFP) or together with human PON3 (AdPON3). Three weeks after injection, lesion area was significantly lower in AdPON3-treated mice compared with AdGFP controls. Serum from AdPON3 mice contained significantly lower levels of lipid hydroperoxides and exhibited an enhanced potential to efflux cholesterol from cholesterol-loaded macrophages. In addition, LDL was less susceptible to oxidation, whereas HDL was more capable of protecting against LDL oxidation. Exogenous human PON3 was not detected in the serum or HDL and more surprisingly we demonstrate that endogenous mouse PON3 is not associated with HDL, suggesting that the antioxidant function of PON3 is at the cellular level in mice.

Conclusions— This study demonstrates for the first time that PON3 enhances the antiatherogenic capacity of serum and protects against the progression of atherosclerosis in vivo.

The objective of this study was to determine whether PON3 can protect against the progression of atherosclerosis in vivo. PON3 overexpression enhances the cholesterol efflux potential of serum, increases the antiinflammatory properties of HDL, and protects against the progression of atherosclerosis in vivo.

Key Words: paraoxonase • atherosclerosis • lipoproteins • oxidative stress • antioxidants