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

Rozenn Quarck, Bart De Geest, Dominique Stengel, Ann Mertens, Marleen Lox, Gregor Theilmeier, Carine Michiels, Martine Raes, Hidde Bult, Désiré Collen, Paul Van Veldhoven, Ewa Ninio, Paul Holvoet

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Abstract

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 (5 × 108 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.

Original languageEnglish
Pages (from-to)2495-2500
Number of pages6
JournalCirculation
Volume103
Issue number20
Publication statusPublished - 22 May 2001

Keywords

  • Atherosclerosis
  • Lipoproteins
  • Restenosis

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    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. (2001). Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice. Circulation, 103(20), 2495-2500.