Adenovirus-mediated gene transfer of Lp-PLA sub(2) reduces LDL degradation and foam cell formation in vitro

• Published in: Journal of lipid research Vol. 45; no. 9; pp. 1633 - 1639
• Main Authors: Turunen, Paeivi, Jalkanen, Johanna, Heikura, Tommi, Puhakka, Hanna, Karppi, Jouni, Nyyssoenen, Kristiina, Ylae-Herttuala, Seppo
• Format: Journal Article
• Language: English
• Published: 01.09.2004
• Subjects: Adenovirus
• ISSN: 0022-2275; 1539-7262

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 A sub(2) (Lp-PLA sub(2)), an enzyme capable of hydrolyzing PAF-like phospholipids. In this study, we generated an adenovirus (Ad) encoding human Lp-PLA sub(2) and injected 10 super(8), 10 super(9), and 10 super(10) plaque-forming unit doses of Adlp-PLA sub(2) and control AdlacZ intra-arterially into rabbits to achieve overexpression of Lp- PLA sub(2) in liver and in vivo production of Lp-PLA sub(2)-enriched LDL. As a result, LDL particles with 3-fold increased Lp-PLA sub(2) activity were produced with the highest virus dose. Increased Lp-PLA sub(2) 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-PLA sub(2) activity. Lipid accumulation and foam cell formation in RAW 264 macrophages were also decreased when incubated with oxidized LDL containing the highest Lp- PLA sub(2) activity. Inhibition of the Lp-PLA sub(2) activity in the LDL particles led to an increase in lipid accumulation and foam cell formation. It is concluded that increased Lp-PLA sub(2) activity in LDL attenuates foam cell formation and decreases LDL oxidation and subsequent degradation in macrophages.