Abstract 1608: Paraoxonase 2 Deficiency Alters Mitochondrial Function and Exacerbates the Development of Atherosclerosis
Objective: Functional abnormalities of mitochondrial electron transport chain (ETC) complexes resulting in increased production of reactive oxygen species (ROS) play an important role in the development of many inflammatory diseases including atherosclerosis. Paraoxonase 2 (PON2) is a ubiquitously expressed intracellular lipo-lactonase with undefined antioxidant properties. PON2 deficient (PON2-def) C57BL/6J mice accumulate elevated levels of ROS in circulation and tissues, and develop aggravated atherosclerotic lesions compared to control mice fed an atherogenic diet. The mechanism whereby the absence of PON2 contributes to oxidative stress is unclear.
Methods and Results: In this report, we demonstrate that PON2-def mice on the hyperlipidemic apoE null background (PON2-def/apoE−/−) develop exacerbated atherosclerotic lesions both on the chow diet and western diet (p<0.05). The heightened lesions in PON2-def/apoE−/− mice were independent of lipoprotein cholesterol levels but correlated with lipoprotein inflammatory properties. We show, for the first time, that PON2 protein is associated with respiratory complex III of the inner mitochondrial membrane. Moreover, ETC complex I+III (NADH-cytochrome C Reductase) and complex IV (Cytochrome Oxidase) activities were significantly reduced (p<0.05) in PON2-def mice compared to wild type mice fed an atherogenic diet indicative of impaired function. Furthermore, mitochondria from PON2-def mice fed an atherogenic diet show significantly elevated levels of malondialdehyde formation and reduced glutathione accumulation indicative of oxidative stress. In contrast, overexpression of PON2 protected mitochondria from H2O2 mediated oxidative stress.
Conclusion: Our results illustrate that the anti-atherogenic effects of PON2 may, in part, be mediated by its role in mitochondrial function.