Local expression of platelet-activating factor-acetylhydrolase reduces accumulation of oxidized lipoproteins and inhibits inflammation, shear stress-induced thrombosis, and neointima formation in balloon-injured carotid arteries in nonhyperlipidemic rabbits

被引:39
作者
Arakawa, H
Qian, JY
Baatar, D
Karasawa, K
Asada, Y
Sasaguri, Y
Miller, ER
Witztum, JL
Ueno, H [1 ]
机构
[1] Univ Occupat & Environm Hlth, Sch Med, Dept Biochem & Mol Pathophysiol, Kitakyushu, Fukuoka 8078555, Japan
[2] Univ Occupat & Environm Hlth, Sch Med, Dept Pathol, Kitakyushu, Fukuoka 8078555, Japan
[3] Teikyo Univ, Fac Pharmaceut Sci, Kanagawa, Japan
[4] Miyazaki Med Coll, Dept Pathol, Miyazaki 88916, Japan
[5] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
关键词
gene therapy; inflammation; lipoproteins; thrombosis; platelet activating factor;
D O I
10.1161/CIRCULATIONAHA.104.476242
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background - Platelet- activating factor ( PAF) and PAF- like phospholipids are inactivated by PAF- acetylhydrolase ( PAF- AH). Using nonhyperlipidemic animals, we tested whether local expression of PAF- AH into injured arteries might induce antithrombotic and antiinflammatory effects. Method and Results - Balloon- injured rabbit carotid arteries were infected at the time of injury with an adenovirus expressing either human plasma PAF- AH ( AdPAF- AH) or bacterial beta- galactosidase ( AdLacZ) or infused with saline. Seven days later, shear stress - induced thrombosis was observed in all AdLacZ- infected and saline- infused arteries ( controls) but eliminated in AdPAF- AH - treated contralateral arteries, even in the presence of epinephrine or an inhibitor of NO production. Injury- induced expression of tissue factor was also significantly suppressed. In AdPAF- AH - treated arteries compared with controls, the expressions of intercellular adhesion molecule- 1 and vascular cell adhesion molecule- 1 and macrophage infiltration were decreased by 66%, 66%, and 71%, respectively ( P < 0.01), and intimal area and intima/ media ratio were decreased on day 21 by 43% and 52%, respectively ( P < 0.05). Within 1 week after injury, oxidized lipoproteins ( OxLDL) had readily accumulated in the arterial wall. However, this was markedly reduced in the AdPAF- AH - treated arteries. No differences in the titers of autoantibodies to OxLDL or total cholesterol in blood were found between controls and AdPAF- AH - treated rabbits. Conclusions - Our results show for the first time that OxLDL accumulates in arteries in nonhyperlipidemic animals within 1 week after injury and that local expression of PAF- AH reduces this accumulation and exerts antiinflammatory, antithrombotic, and antiproliferative effects without changing the plasma levels of PAF- AH activity or titers of autoantibodies to OxLDL.
引用
收藏
页码:3302 / 3309
页数:8
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