Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro- or anti-atherogenic effects, depend ing on its localization. Decreased plasma LPL activity is associated with t he high triglyceride (TG)-low HDL phenotype that is often observed in patie nts with premature vascular disease. In contrast, in the vessel wall, decre ased LPL may be associated with less lipoprotein retention due to many pote ntial mechanisms and, therefore, decreased foam cell formation. To directly assess this hypothesis, we have distinguished between the effects of varia tions in plasma and/or vessel wall LPL on atherosclerosis susceptibility in apoE-deficient mice. Reduced LPL in both plasma and vessel wall (LPL+/- E- /-) was associated with increased TG and increased total cholesterol (TC) c ompared with LPL+/+E-/- sibs, However despite their dyslipidemia, LPL+/-E-/ - mice had significantly reduced lesion areas compared to the LPL(+/+)E(-/- )mice. Thus, decreased vessel wall LPL was associated with decreased lesion formation even in the presence of reduced plasma LPL activity. In contrast , transgenic mice with increased plasma LPL but with no increase in LPL exp ression in macrophages, and thus the vessel wall, had decreased TG and TC a nd significantly decreased lesion areas compared with LPL+/+E-/- mice. This demonstrates that increased plasma LPL activity alone, in the absence of a n increase in vessel wall LPL, is associated with reduced susceptibility to atherosclerosis. Taken together these results provide in vivo evidence tha t the contribution of LPL to atherogenesis is significantly influenced by t he balance between vessel wall protein (pro-atherogenic) and plasma activit y (anti-atherogenic).