Abstract 1276: Inactivation of Endothelial Lipase Increases Anti-inflammatory HDL Particles
Background: Recent studies have indicated the presence of “dysfunctional” HDL particles, which lack in anti-inflammatory and anti-atherosclerotic properties, in patients with cardiovascular diseases. Endothelial lipase (EL) is a determinant of the plasma high-density lipoprotein (HDL) level, and is a candidate molecule in the HDL-raising pharmaceutical therapy. Although EL−/− mice are high in plasma HDL levels, little is known concerning the quality of HDL particles after EL inactivation. In this study, we assessed the effect of EL inactivation on anti-atherosclerotic properties of HDL particles.
Methods and Results: Whole plasma or HDL samples were obtained from EL−/− and EL+/+ mice. The HDL quality was assessed by evaluating lipopolysaccharide (LPS)-neutralizing capacity, inhibition of cytokine-induced VCAM-1 expression, inhibition of LDL-oxidation, activities of HDL-associated anti-oxidative enzymes (PON1 and PAF-AH), and the ability of cholesterol efflux. The limulus amebocyte lysate (LAL) activity assay revealed that the LPS-neutralizing capacity of the whole plasma and HDL from EL −/− mice was significantly higher than those in EL+/+ mice. In addition, PON1 and PAF-AH activities were significantly increased in the whole plasma of EL−/− mice than those in WT mice, and the increased enzymatic activities were in proportion to the plasma HDL-cholesterol levels in these mice. Furthermore, the ability of cholesterol efflux, inhibition of VCAM-1 expression, and inhibition of LDL-oxidation was similar in HDL fractions obtained from EL−/− and EL+/+ mice. To evaluate the anti-inflammatory action of HDL was evaluated in vivo, LPS-induced systemic inflammation was generated in these mice. Expression of inflammatory markers such as VCAM-1 and iNOS was lower, and survival rate was higher in EL−/− mice than EL+/+ mice.
Conclusions: EL inactivation increases HDL-cholesterol particles that have a variety of anti-inflammatory or anti-oxidative properties in mice. EL−/− mice are protected against systemic inflammation. Thus, EL would be a target for raising “good cholesterol.”