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J. Biol. Chem., Vol. 281, Issue 40, 29491-29500, October 6, 2006

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Paraoxonase-2 Deficiency Aggravates Atherosclerosis in Mice Despite Lower Apolipoprotein-B-containing Lipoproteins

ANTI-ATHEROGENIC ROLE FOR PARAOXONASE-2^*

Carey J. Ng, Noam Bourquard, Victor Grijalva, Susan Hama, Diana M. Shih, Mohamad Navab, Alan M. Fogelman, Aldons J. Lusis, Stephen Young, and Srinivasa T. Reddy¹

From the Departments of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California 90095

Paraoxonases (PONs) are a family of proteins that may play a significant role in providing relief from both toxic environmental chemicals as well as physiological oxidative stress. Although the physiological roles of the PON family of proteins, PON1, PON2, and PON3, remain unknown, epidemiological, biochemical, and mouse genetic studies of PON1 suggest an anti-atherogenic function for paraoxonases. To determine whether PON2 plays a role in the development of atherosclerosis in vivo, we generated PON2-deficient mice. When challenged with a high fat, high cholesterol diet for 15 weeks, serum levels of high density lipoprotein cholesterol, triglycerides, and glucose were not significantly different between wild-type and PON2-deficient mice. In contrast, serum levels of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) cholesterol were significantly lower (–32%) in PON2-deficient mice compared with wild-type mice. However, despite lower levels of VLDL/LDL cholesterol, mice deficient in PON2 developed significantly larger (2.7-fold) atherosclerotic lesions compared with their wild-type counterparts. Enhanced inflammatory properties of LDL, attenuated anti-atherogenic capacity of high density lipoprotein, and a heightened state of oxidative stress coupled with an exacerbated inflammatory response from PON2-deficient macrophages appear to be the main mechanisms behind the larger atherosclerotic lesions in PON2-deficient mice. These results demonstrate that PON2 plays a protective role in atherosclerosis.

Received for publication, June 5, 2006 , and in revised form, August 4, 2006.

^* This work was supported by NHLBI, National Institutes of Health Grants 1RO1HL71776, HL-30568, and by the Laubisch, Castera, and M. K. Grey Funds at UCLA. 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.

¹ To whom correspondence should be addressed: Division of Cardiology, Dept. of Medicine, UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095. Tel.: 310-206-3915; Fax: 310-206-3605; E-mail: sreddy{at}mednet.ucla.edu.

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