Gene delivery of paraoxonase-1 inhibits neointimal hyperplasia after arterial balloon-injury in rabbits fed a high-fat diet

Abstract

Paraoxonase-1 (PON-1) is a high-density lipoprotein (HDL)-associated enzyme that hydrolyzes oxidized phospholipids, thereby preventing the oxidative modification of low-density lipoproteins (LDL). A high-fat diet reduces PON-1 activity, enhancing LDL oxidation. Thus, PON-1 is a candidate for anti-etherogenic gene therapy. In the present study, we investigated the effect of local PON-1 overexpression on the development of atherosclerotic lesions using the Sendai virus-mediated transgenic technique. One-month-old rabbits (n=11) were fed a high-fat diet for 8 weeks and then subjected to balloon injury of the common iliac artery and simultaneous infection with a Sendai virus vector containing the PON-1 gene (n=7) or enhanced green fluorescence protein (EGFP) gene as a control (n=4). The arteries were examined 7-10 days after the operation. Local overexpression of PON-1 almost completely eliminated the immunohistochemical signals of the lectin-like oxidized LDL receptor-1 (LOX-1), thereby inhibiting macrophage accumulation, intimal thickening (by 63% compared with control), or atherosclerotic plaque formation in the vascular lumen (by 87.5%). Decreased levels of oxidative stress in the PON-1-treated arteries were confirmed by 4-hydroxy-2-nonenal (HNE) staining. Local overexpression of PON-1 in the arteries attenuated oxidative stress, thereby inhibiting the atheroeclerotic process. Delivery of the PON-1 gene may be a possible therapeutic strategy for preventing atherosclerosis.