HDL-associated PAF-AH reduces endothelial adhesiveness in apoE(-/-) mice

Macrophage infiltration into the subendothelial space at lesion prone sites is the primary event in atherogenesis. Inhibition of macrophage homing mig ht therefore prevent atherosclerosis. Since HDL levels are inversely correl ated with cardiovascular risk, their effect on macrophage homing was assess ed in apoE-deficient (apoE(-/-)) mice. Overexpression of human apolipoprote in AI in apoE(-/-) mice increased HDL levels 3-fold and reduced macrophage accumulation in an established assay of leukocyte homing to aortic root end othelium 3.2-fold (P<0.005). This was due to reduced in vivo beta VLDL oxid ation, reduced beta VLDL triggered endothelial cytosolic Ca2+ signaling thr ough PAF-like bioactivity, lower ICAM-1 and VCAM-1 expression, and diminish ed ex vivo leukocyte adhesion. Adenoviral gene transfer of human PAF-acetyl hydrolase (PAF-AH) in apoE(-/-) mice increased PAF-AH activity 1.5-fold (P< 0.001), reduced beta VLDL-induced ex vivo macrophage adhesion 3.5-fold (P<0 .01), and reduced in vivo macrophage homing 2.6-fold (P<0.02). These inhibi tory effects were observed in the absence of increased HDL cholesterol leve ls. In conclusion, HDL reduces macrophage homing to endothelium by reducing oxidative stress via its associated PAF-AH activity. This protective mecha nism is independent of the function of HDL as cholesterol acceptor. Modulat ion of lipoprotein oxidation by PAF-AH may prevent leukocyte recruitment to the vessel wall, a key feature in atherogenesis.