Intravascular adenovirus-mediated lipoprotein-associated phospholipase A 2 gene transfer reduces neointima formation in balloon-denuded rabbit aorta

Abstract

Postangioplasty restenosis is a multifactorial process and involves mechanisms such as inflammation and stimulation of the expression of growth factors. Lipoprotein-associated phospholipase A 2 (Lp-PLA 2) can modify inflammatory responses by hydrolyzing phospholipids with shortened and/or oxidized sn-2 residues. In this study, we tested a hypothesis that adenovirus-mediated Lp-PLA 2 gene transfer can reduce restenosis in rabbits. Aortas of cholesterol-fed NZW rabbits were balloon-denuded and intra-arterial gene transfer was performed using Dispatch catheter with Lp-PLA 2 or LacZ adenoviruses (1.15 × 10 10 pfu). Intima/media ratio (I/M), histology and cell proliferation were analyzed. Two weeks after the gene transfer I/M in the LacZ-transduced control group was 0.45 ± 0.05 but Lp-PLA 2 gene transfer reduced I/M to 0.25 ± 0.03. At four weeks time point I/M in the Lp-PLA 2 group (0.34 ± 0.05) was also lower than in the LacZ group (0.53 ± 0.06). Plasma Lp-PLA 2 activity was increased in the Lp-PLA 2 group (48.2 ± 4.2) as compared to the LacZ group (33.6 ± 3.51) at two weeks time point. Transgene expression was detected in the arterial wall two and four weeks after the procedure. Apoptosis was higher in the control vessels than in the Lp-PLA 2 group at two weeks time point. In conclusion, local adenovirus-mediated Lp-PLA 2 gene transfer resulted in a significant reduction in neointima formation in balloon-denuded rabbit aorta and may be useful for the prevention of restenosis after arterial manipulations.