Paraoxonase 1 Interactions with HDL, Antioxidants and Macrophages Regulate Atherogenesis – A Protective Role for HDL Phospholipids

Macrophage cholesterol accumulation and foam cell formation is the hallmark of early atherogenesis. In addition to macrophages, at least three more major players regulate atherosclerosis development; paraoxonase 1 (PON1), antioxidants, and HDL. PON1 is an HDL-associated lactonase which posses antioxidant and anti-atherogenic properties. PON1 protects against macrophage-mediated LDL oxidation, and increases HDL binding to macrophages which, in turn, stimulates HDL's ability to promote cholesterol efflux. These two major anti-atherogenic properties of HDL (and of PON1) require, at least in part, macrophage binding sites for HDL-associated PON1. Indeed, PON1, as well as HDL-associated PON1, specifically binds to macrophages, leading to anti-atherogenic effects. Macrophage PON1 binding sites may thus be a target for future cardioprotection therapy. Studying the interactions among PON1, antioxidants, and macrophages can thus assist in achieving appropriate treatment and prevention of atherosclerosis.