(Circulation. 2001;103:2495.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Adenovirus-Mediated Gene Transfer of Human Platelet-Activating Factor–Acetylhydrolase Prevents Injury-Induced Neointima Formation and Reduces Spontaneous Atherosclerosis in Apolipoprotein E–Deficient Mice
From the Center for Molecular and Vascular Biology (R.Q., B.D.G., A.M., M.L., G.T., D.C., P.H.), the Department of Experimental Surgery and Anesthesiology (R.Q., A.M., M.L., P.H.), and the Department of Molecular Cell Biology, Division of Pharmacology (P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; INSERM U525, Institut Fédératif "Muscle Coeur et Vaisseaux," Faculté de Médecine Pitié-Salpétrière, Université Pierre et Marie Curie, Paris, France (D.S., E.N.); Laboratoire de Biochimie et de Biologie Cellulaire, FUNDP, Namur, Belgium (C.M., M.R.); and the Department of Pharmacology, University of Antwerpen, Antwerpen, Belgium (H.B.).
Correspondence to Dr P. Holvoet, Department of Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N, Herestraat 49, B-3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.ac.be
Background—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.
Methods and Results—Intravenous administration of an adenovirus (5x108 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).
Conclusions—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.
Key Words: atherosclerosis • lipoproteins • restenosis
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