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

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 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).

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.

• Authors: R Quarck, B De Geest, D Stengel, A Mertens, M Lox, G Theilmeier, C Michiels, M Raes, H Bult, D Collen, P Van Veldhoven, E Ninio, P Holvoet
• Journal: Circulation (Circulation) Vol. 103 Issue 20 Pg. 2495-500 (May 22 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11369691 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Cholesterol, HDL
• Cholesterol, VLDL
• RNA
• Phospholipases A
• 1-Alkyl-2-acetylglycerophosphocholine Esterase

Topics

• 1-Alkyl-2-acetylglycerophosphocholine Esterase
• Adenoviridae (genetics)
• Animals
• Apolipoproteins E (deficiency, genetics)
• Arteriosclerosis (genetics, prevention & control)
• Cholesterol, HDL (blood)
• Cholesterol, VLDL (blood)
• Female
• Gene Expression
• Gene Transfer Techniques
• Genetic Vectors (genetics)
• Humans
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Oxidative Stress (genetics)
• Phospholipases A (blood, genetics)
• RNA (genetics, metabolism)
• Time Factors
• Tunica Intima (metabolism, pathology)