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

Journal of Lipid Research

Tommi Heikura¹  Seppo Ylä-Herttuala¹  Hanna Puhakka²  Johanna Jalkanen³  Kristiina Nyyssönen³  Jouni Karppi⁴  Päivi Turunen⁴ 

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

关键词: lipoprotein-associated phospholipase A2;    low density lipoprotein;    macrophage;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown