Quarck R, De Geest B, Stengel D, Mertens A, Lox M, Theilmeier G, Michiels C, Raes M, Bult H, Collen D, Van Veldhoven P, Ninio E, Holvoet P
Center for Molecular and Vascular Biology, Department of Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Leuven, Belgium.
Circulation. 2001 May 22;103(20):2495-500. doi: 10.1161/01.cir.103.20.2495.
Atherosclerosis is characterized by an early inflammatory response involving proinflammatory mediators such as platelet-activating factor (PAF)-like phospholipids, which are inactivated by PAF-acetylhydrolase (PAF-AH). The effect of adenovirus-mediated expression of PAF-AH on injury-induced neointima formation and spontaneous atherosclerosis was studied in apolipoprotein E-deficient mice.
Intravenous administration of an adenovirus (5 x 10(8) plaque-forming units) directing liver-specific expression of human PAF-AH resulted in a 3.5-fold increase of plasma PAF-AH activity at day 7 (P<0.001); this was associated with a 2.4- and 2.3-fold decrease in malondialdehyde-modified LDL autoantibodies and the lysophosphatidylcholine/phosphatidylcholine ratio, respectively (P<0.001 for both). Non-HDL and HDL cholesterol levels in PAF-AH-treated mice were similar to those of control virus-treated mice. Seven days after virus injection, endothelial denudation of the common left carotid artery was induced with a guidewire. Neointima formation was assessed 18 days later. PAF-AH gene transfer reduced oxidized lipoproteins by 82% (P<0.001), macrophages by 69% (P=0.006), and smooth muscle cells by 84% (P=0.002) in the arterial wall. This resulted in a 77% reduction (P<0.001) of neointimal area. Six weeks after adenovirus-mediated gene transfer, spontaneous atherosclerotic lesions in the aortic root were analyzed. PAF-AH gene transfer reduced atherosclerotic lesions by 42% (P=0.02) in male mice, whereas a nonsignificant 14% reduction was observed in female mice. Basal and PAF-AH activity after gene transfer were higher in male mice than in female mice (P=0.01 and P=0.04, respectively).
Gene transfer of PAF-AH inhibited injury-induced neointima formation and spontaneous atherosclerosis in apolipoprotein E-deficient mice. Our data indicate that PAF-AH, by reducing oxidized lipoprotein accumulation, is a potent protective enzyme against atherosclerosis.
动脉粥样硬化的特征是早期炎症反应，涉及血小板活化因子（PAF）样磷脂等促炎介质，这些介质可被PAF - 乙酰水解酶（PAF - AH）灭活。我们在载脂蛋白E缺乏的小鼠中研究了腺病毒介导的PAF - AH表达对损伤诱导的新生内膜形成和自发性动脉粥样硬化的影响。
静脉注射一种指导人PAF - AH肝脏特异性表达的腺病毒（5×10⁸ 空斑形成单位），在第7天时血浆PAF - AH活性增加3.5倍（P<0.001）；这分别与丙二醛修饰的低密度脂蛋白自身抗体和溶血磷脂酰胆碱/磷脂酰胆碱比值降低2.4倍和2.3倍相关（两者均P<0.001）。PAF - AH处理小鼠的非高密度脂蛋白和高密度脂蛋白胆固醇水平与对照病毒处理小鼠相似。病毒注射7天后，用导丝诱导左颈总动脉内皮剥脱。18天后评估新生内膜形成情况。PAF - AH基因转移使动脉壁中的氧化脂蛋白减少82%（P<0.001），巨噬细胞减少69%（P = 0.006），平滑肌细胞减少84%（P = 0.002）。这导致新生内膜面积减少77%（P<0.001）。腺病毒介导的基因转移6周后，分析主动脉根部的自发性动脉粥样硬化病变。PAF - AH基因转移使雄性小鼠的动脉粥样硬化病变减少42%（P = 0.02），而在雌性小鼠中观察到14%的减少但无统计学意义。基因转移后雄性小鼠的基础和PAF - AH活性高于雌性小鼠（分别为P = 0.01和P = 0.04）。
PAF - AH基因转移抑制了载脂蛋白E缺乏小鼠中损伤诱导的新生内膜形成和自发性动脉粥样硬化。我们的数据表明，PAF - AH通过减少氧化脂蛋白的积累，是一种有效的抗动脉粥样硬化保护酶。
