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

Oxidation of LDL generates biologically active platelet-activating factor (PAF)-like phospholipid deriva- tives, which have potent proinflammatory activity. These products are inactivated by lipoprotein-associated phospho- lipase A 2 (Lp-PLA 2 ), an enzyme capable of hydrolyzing PAF- like phospholipids. In this study, we generated an adeno- virus (Ad) encoding human Lp-PLA 2 and injected 10 8 , 10 9 , and 10 10 plaque-forming unit doses of Adlp-PLA 2 and con- trol AdlacZ intra-arterially into rabbits to achieve overex- pression of Lp-PLA 2 in liver and in vivo production of Lp- PLA 2 -enriched LDL. As a result, LDL particles with 3-fold increased Lp-PLA 2 activity were produced with the highest virus dose. Increased Lp-PLA 2 activity in LDL particles de- creased 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 2 activity. Lipid accumulation and foam cell formation in RAW 264 macrophages were also decreased when incubated with oxi- dized LDL containing the highest Lp-PLA 2 activity. Inhibi- tion of the Lp-PLA 2 activity in the LDL particles led to an in- crease in lipid accumulation and foam cell formation. It is concluded that increased Lp-PLA 2 activity in LDL attenu- ates foam cell formation and decreases LDL oxidation and subsequent degradation in macrophages. —Turunen, P., J. Jalkanen, T. Heikura, H. Puhakka, J. Karppi, K. Nyyssonen, and S. Yla-Herttuala. Adenovirus-mediated gene transfer of Lp-PLA 2 reduces LDL degradation and foam cell formation in vitro. J. Lipid Res. 2004. 45: 1633-1639.