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

Abstract

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 2 (Lp-PLA 2 ), an enzyme capable of hydrolyzing PAFlike phospholipids. In this study, we generated an adenovirus (Ad) encoding human Lp-PLA 2 and injected 10 8 , 10 9 , and 10 10 plaque-forming unit doses of Adlp-PLA 2 and control AdlacZ intra-arterially into rabbits to achieve overexpression 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 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 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 2 activity. Inhibition of the Lp-PLA 2 activity in the LDL particles led to an increase in lipid accumulation and foam cell formation. It is concluded that increased Lp-PLA 2 activity in LDL attenuates foam cell formation and decreases LDL oxidation and subsequent degradation in macrophages. -Turunen, P., J. Jalkanen, T. Heikura, H. Puhakka, J. Karppi, K. Nyyssönen, and S. Ylä-Herttuala. Adenovirus-mediated gene transfer of Lp-PLA 2 reduces LDL degradation and foam cell formation in vitro.

Carboxyl Ester Lipase Expression in Macrophages Increases Cholesteryl Ester Accumulation and Promotes Atherosclerosis

“…In fact, results of the current study suggest that LPC may be anti-atherogenic under selected circumstances, such as in hypercholesterolemia where the cholesterol is esterified in macrophages to induce foam cells. Reports showing LPC promotion of cholesterol efflux from macrophage foam cells (39) and the ability of lipoprotein-associated phospholipase A 2 to reduce LDL degradation and foam cell formation in vitro (40) are supportive of this hypothesis. In summary, our data documented that macrophage expression of CEL is pro-atherogenic, favoring cholesteryl ester accumulation and foam cell formation to increase atherosclerosis lesions in mice.…”

Comprehensive Evaluation of Genetic and Environmental Factors Influencing the Plasma Lipoprotein-Associated Phospholipase A2 Activity in a Japanese Population

“…In contrast, studies on Japanese subjects indicated that those with the minor allele were more susceptible to coronary heart diseases (17,21) and cerebral stroke (22). Although the sizes of the populations employed in these genetic studies might not have been large enough to ensure analytical power, the results of an in vitro study support the notion of a protective role of Lp-PLA2 against atherosclerosis (3).…”

The emerging roles of PAF acetylhydrolase

“…The reduction in atherogenicity in these models derives from plasma PAF-AH remodeling of lipoprotein particles after oxidation, rather than a direct effect on vascular cells, because lipoproteins isolated from animals transiently overexpressing PAF-AH are less able to induce foam cell formation in an in vitro model (33,34). The kinetics of lipid oxidation during the development of atherosclerotic lesions provide additional important clues regarding the role of PAF-AH in this syndrome.…”