D-4F Increases Paraoxonase 1 Activity in HDL

Abstract

HDL, apoA-I, and apoA-I mimetic peptides have been shown to prevent LDL oxidation in cell-free systems and in the artery wall coculture studies. Moreover, HDL, apoA-I, and apoA-I mimetics have been shown to decrease lesions and improve vascular reactivity in animal models of atherosclerosis and in humans. The primary mechanism by which HDL and apoA-I and apoA-I mimetic peptides exert their beneficial effect has been presumed to be the enhancement of reverse cholesterol transport. However, apoA-I has also been shown to be capable of removing “seeding molecules” from LDL, thus preventing the oxidation of LDL-derived phospholipids to those that are thought to be responsible for the inflammatory response characteristic of atherosclerosis. D-4F is an apoA-I mimetic peptide that demonstrates many of the properties of apoA-I itself. Oral D-4F increases paraoxonase activity in monkeys and causes the formation of pre-s HDL. When added in nanomolar amounts to normal human plasma, D-4F reduces lipoprotein lipid hydroperoxide content, increases paraoxonase activity, and converts proinflammatory HDL to anti-inflammatory. Adding the combination of D-4F and pravastatin to mouse chow synergized to result in a significant increase in apoA-I levels, HDL-cholesterol, and paraoxonase activity in old apoE-null mice. We have shown that incubation of HDL from human patients or apoE deficient mouse with D-4F results in reduction of lipid hydroperoxides and an increase in paraoxonase activity in HDL