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
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
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DOI：
10.1161/circulationaha.104.476242
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发表时间：
2005-06-21
期刊：
影响因子：
37.8
通讯作者：
Ueno, H
中科院分区：
文献类型：
--
作者：
Arakawa, H;Qian, JY;Ueno, H
血小板活化因子（PAF）和PAF样磷脂被PAF乙酰水解酶（PAF-AH）灭活.使用nonhypertrophemic动物，我们测试是否局部表达的PAF- AH到受伤的动脉可能会引起抗血栓形成和抗血栓形成effects.Method and Results -球囊损伤兔颈动脉感染时，损伤与腺病毒表达人血浆PAF- AH（AdPAF- AH）或细菌β-半乳糖苷酶（AdLacZ）或注入盐水。7天后，在所有AdLacZ感染和盐水灌注的动脉（对照）中观察到剪切应力诱导的血栓形成，但在AdPAF-AH处理的对侧动脉中消除，即使在肾上腺素或NO产生抑制剂存在下也是如此.损伤诱导的组织因子表达也被显著抑制。与对照组相比，AdPAF-AH组细胞间粘附分子-1、血管细胞粘附分子-1的表达和巨噬细胞浸润分别减少66%、66%和71%（P < 0.01），内膜面积和内膜/中膜比值分别减少43%和52%（P < 0.05）。损伤后1周内，氧化脂蛋白（OxLDL）已很容易积聚在动脉壁。然而，在AdPAF-AH处理的动脉中，这显著降低。对照组和AdPAF-AH治疗组家兔血液中OxLDL或总胆固醇自身抗体滴度无差异。结论-我们的研究结果首次表明，OxLDL在非高脂血症动物损伤后1周内在动脉中积累，并且PAF-AH的局部表达减少了这种积累，并发挥抗血栓，抗血栓形成，和抗增殖作用而不改变血浆PAF-AH活性水平或OxLDL自身抗体滴度。
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.