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-atherogenic 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 atherosclerotic process. Delivery of the PON-1 gene may be a possible therapeutic strategy for preventing atherosclerosis.

• Authors: Miwa Miyoshi, Yukiko Nakano, Takemasa Sakaguchi, Hiroshi Ogi, Noboru Oda, Kazuyoshi Suenari, Katsuhiro Kiyotani, Ryoji Ozono, Tetsuya Oshima, Tetsuya Yoshida, Kazuaki Chayama
• Journal: Hypertension research : official journal of the Japanese Society of Hypertension (Hypertens Res) Vol. 30 Issue 1 Pg. 85-91 (Jan 2007) ISSN: 0916-9636 [Print] England
• PMID: 17460375 (Publication Type: Journal Article)

Chemical References

• Dietary Fats
• Lipids
• Lipoproteins
• Matrix Metalloproteinase Inhibitors
• Scavenger Receptors, Class E
• Aryldialkylphosphatase

Topics

• Animals
• Aryldialkylphosphatase (genetics, metabolism, pharmacology)
• Atherosclerosis (prevention & control)
• Catheterization
• Cell Line
• Dietary Fats (administration & dosage)
• Gene Transfer Techniques
• Genetic Vectors
• Hyperplasia
• Iliac Artery (drug effects, metabolism, pathology)
• Lipids (blood)
• Lipoproteins (blood)
• Male
• Matrix Metalloproteinase Inhibitors
• Oxidative Stress (drug effects)
• Rabbits
• Rats
• Scavenger Receptors, Class E (antagonists & inhibitors)
• Sendai virus (genetics)
• Tunica Intima (drug effects, pathology)