Gene delivery of paraoxonase-1 inhibits neointimal hyperplasia after arterial balloon-injury in rabbits fed a high-fat diet.
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.
Miyoshi
Miwa
M
Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Japan. miwa0081jp@yahoo.co.jp
Nakano
Yukiko
Y
Sakaguchi
Takemasa
T
Ogi
Hiroshi
H
Oda
Noboru
N
Suenari
Kazuyoshi
K
Kiyotani
Katsuhiro
K
Ozono
Ryoji
R
Oshima
Tetsuya
T
Yoshida
Tetsuya
T
Chayama
Kazuaki
K
D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D050197:Atherosclerosis / Q000517:prevention & control*; D002404:Catheterization; D002460:Cell Line; D004041:Dietary Fats / Q000008:administration & dosage*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006965:Hyperplasia; D007083:Iliac Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors; D029082:Sendai virus / Q000235:genetics; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
D004041:Dietary Fats; D008055:Lipids; D008074:Lipoproteins; D061965:Matrix Metalloproteinase Inhibitors; D051127:Scavenger Receptors, Class E; D043303:Aryldialkylphosphatase