Regulation of the expression of platelet-activating factor (PAF) receptor b
y atherogenic lipoproteins might contribute to atherogenesis. We show that
progressive oxidation of low-density lipoprotein (LDL) gradually inhibits P
AF receptor expression on the macrophage cell surface. We tested the effect
of oxidized LDL (oxLDL) on PAF receptor expression in human monocytes that
do not contain peroxisome-proliferator-activated receptor gamma (PPAR gamm
a), a nuclear receptor activated by oxLDL. OxLDL decreased by 50% (P less t
han or equal to 0.001) and by 29% (P less than or equal to 0.05) the bindin
g of PAF and the expression of PAF receptor mRNA respectively. Next we demo
nstrated that progressive oxidation of LDLs significantly activated PPAR al
pha -dependent transcription in transfected mouse aortic endothelial cells.
Finally we demonstrated, in mature macrophages, that fenofibrate (20 muM),
a specific PPAR alpha agonist, but not the specific PPAR gamma agonist BRL
49653 (20 nM), significantly decreased both PAF binding and PAF receptor mR
NA expression, by 65% and 40% (P less than or equal to 0.001) respectively.
Additionally, another PPAR alpha agonist, Wy14,643, decreased PAF receptor
promoter activity by 70% (P less than or equal to 0.05) in transfected THP
-1 cells, suggesting the involvement of the proximal promoter region (-980
to -500) containing a series of four nuclear factor (NF)-kappaB motifs. Thu
s PPAR alpha might be involved in the down-regulation of PAF receptor gene
expression by oxLDLs in human monocytes/macrophages. The oxidation of one o
r more lipid components of LDLs might result in the formation of natural ac
tivators of PPAR alpha. It is hypothesized that such activators might modul
ate inflammation and apoptosis upon atherogenesis by decreasing the express
ion of PAF receptor.