Paraoxonase 1 (PON1) deficiency in mice is associated with reduced expression of macrophage SR-BI and consequently the loss of HDL cytoprotection against apoptosis.

BACKGROUND: Paraoxonase 1 (PON1) was shown to stimulate HDL binding and HDL-mediated cholesterol efflux from macrophages. This study examined the role of PON1 in the expression of proteins that enhance macrophage HDL binding, i.e. ABCA1 and SR-BI. METHODS AND
RESULTS: ABCA1 expression was similar, whereas SR-BI expression (mRNA and protein determined by FACS, Western blot, or immunocytochemistry) was significantly decreased in peritoneal macrophages from PON1 deficient (MPM-PON1(0)) in comparison to C57Bl/6 (MPM-Control) mice. PON1 deficiency correction with HDL-control, recombinant PON1 (rePON1), or by transfection with a plasmid containing the rePON1 gene, increased SR-BI expression in MPM-PON1(0), whereas rePON1/H115Gln mutant, or the H115Q/H134Q double mutant, which lack catalytic activity, did not stimulate SR-BI expression. Lysophosphatidyl choline (LPC) resulting from PON1 action on macrophage PC, upregulated SR-BI expression in MPM-PON1(0) via activation of ERK1/2 and PI3K. Functionally, HDL bound to MPM-PON1(0) significantly less than to MPM-Control, and failed to inhibit tunicamycin-induced apoptosis, but had no significant effect on HDL-mediated cholesterol efflux from macrophages.
CONCLUSIONS: PON1 deficiency in mice is associated with decreased macrophage SR-BI expression, decreased cellular HDL binding, and consequently the loss of HDL-mediated cytoprotection against apoptosis, which may contribute to the accelerated atherosclerosis observed in PON1(0) mice. These findings add new insights into the function of SR-BI in macrophages, and define the potential role of PON1 in regulating SR-BI-mediated HDL protection against macrophages apoptosis. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.