Intravascular adenovirus-mediated lipoprotein-associated phospholipase A2 gene transfer reduces neointima formation in balloon-denuded rabbit aorta.
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 x 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.
Turunen
Päivi
P
A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.
Puhakka
Hanna
H
Rutanen
Juha
J
Hiltunen
Mikko O
MO
Heikura
Tommi
T
Gruchala
Marcin
M
Ylä-Herttuala
Seppo
S
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000473:pathology / Q000628:therapy*; D002404:Catheterization / Q000009:adverse effects*; D003251:Constriction, Pathologic; D018014:Gene Transfer Techniques; D007763:Lac Operon; D008297:Male; D010741:Phospholipases A / Q000235:genetics*; D054467:Phospholipases A2; D011817:Rabbits; D019076:Transgenes / Q000502:physiology; D017539:Tunica Intima / Q000473:pathology
D010741:Phospholipases A; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase