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.