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Journal of Lipid Research, Vol. 45, 1633-1639, September 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Adenovirus-mediated gene transfer of Lp-PLA₂ reduces LDL degradation and foam cell formation in vitro

Päivi Turunen^*, Johanna Jalkanen^*, Tommi Heikura^*, Hanna Puhakka^*, Jouni Karppi, Kristiina Nyyssönen and Seppo Ylä-Herttuala^1,*,,**

^* A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland
Research Institute of Public Health, University of Kuopio, FIN-70211 Kuopio, Finland
Department of Medicine, University of Kuopio, FIN-70211 Kuopio, Finland
^** Gene Therapy Unit, University of Kuopio, FIN-70211 Kuopio, Finland

¹ To whom correspondence should be addressed. e-mail: seppo.ylaherttuala{at}uku.fi

Oxidation of LDL generates biologically active platelet-activating factor (PAF)-like phospholipid derivatives, which have potent proinflammatory activity. These products are inactivated by lipoprotein-associated phospholipase A₂ (Lp-PLA₂), an enzyme capable of hydrolyzing PAF-like phospholipids. In this study, we generated an adenovirus (Ad) encoding human Lp-PLA₂ and injected 10⁸, 10⁹, and 10¹⁰ plaque-forming unit doses of Adlp-PLA₂ and control AdlacZ intra-arterially into rabbits to achieve overexpression of Lp-PLA₂ in liver and in vivo production of Lp-PLA₂-enriched LDL. As a result, LDL particles with 3-fold increased Lp-PLA₂ activity were produced with the highest virus dose. Increased Lp-PLA₂ activity in LDL particles decreased the degradation rate in RAW 264 macrophages after standard in vitro oxidation to 60–80% compared with LDL isolated from LacZ-transduced control rabbits. The decrease was proportional to the virus dose and Lp-PLA₂ activity. Lipid accumulation and foam cell formation in RAW 264 macrophages were also decreased when incubated with oxidized LDL containing the highest Lp-PLA₂ activity. Inhibition of the Lp-PLA₂ activity in the LDL particles led to an increase in lipid accumulation and foam cell formation.

It is concluded that increased Lp-PLA₂ activity in LDL attenuates foam cell formation and decreases LDL oxidation and subsequent degradation in macrophages.

Abbreviations: Ad, adenovirus; ALAT, alanine aminotransferase; CRP, C-reactive protein; IL-6, interleukin-6; LPDS, lipoprotein-deficient serum; Lp-PLA₂, lipoprotein-associated phospholipase A₂; lyso-PC, lysophosphatidylcholine; oxLDL, oxidized low density lipoprotein; PAF-AH, platelet-activating factor-acetylhydrolase; pfu, plaque-forming units; SMC, smooth muscle cell; TBARS, thiobarbituric acid-reactive substance

Supplementary key words lipoprotein-associated phospholipase A₂ • low density lipoprotein • macrophage

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