Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice

Background-Atherosclerosis is characterized by an early inflammatory respon se 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-induc ed neointima formation and spontaneous atherosclerosis was studied in apoli poprotein E-deficient mice. Methods and Results-Intravenous administration of an adenovirus (5x10(8) pl aque-forming units) directing liver-specific expression of human PAF-AH res ulted 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-mo dified LDL autoantibodies and the lysophosphatidylcholine/phosphatidylcholi ne ratio, respectively (P<0.001 for both). Non-HDL and HDL cholesterol leve ls in PAF-AH-treated mice were similar to those of control virus-treated mi ce. Seven days after virus injection, endothelial denudation of the common left carotid artery was induced with a guidewire. Neointima formation was a ssessed 18 days later. PAF-AH gene transfer reduced oxidized lipoproteins b y 82% (P<0.001), macrophages by 69% (P=0.006), and smooth muscle cells by 8 4% (P=0.002) in the arterial wall. This resulted in a 77% reduction (P<0.00 1) of neointimal area. Six weeks after adenovirus-mediated gene transfer, s pontaneous 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 f emale mice (P=0.01 and P=0.04, respectively). Conclusions-Gene transfer of PAF-AH inhibited injury-induced neointima form ation and spontaneous atherosclerosis in apolipoprotein E-deficient mice, O ur data indicate that PAF-AH, by reducing oxidized lipoprotein accumulation , is a potent protective enzyme against atherosclerosis.