Lipoprotein-induced prostacyclin production in endothelial cells
and the effects of lipoprotein modification.
Myers, Damian E., Wei-Ning Huang, and Richard G. Larkins.
Department of Medicine, University of Melbourne, Royal Melbourne
Hospital, Parkville, Victoria, Australia, 3052
APStracts 3:0170C, 1996.
Lipoproteins facilitate lipid delivery and uptake via specific cell
receptors. While lipoprotein modification leading to unregulated cell
uptake of cholesterol into foam cells has been described, the effects
of modified forms of lipoproteins on vascular cell function has not
been fully resolved. We have investigated lipoprotein-induced
prostaglandin production by macrovascular endothelial cells. This
study delineates early responses of endothelial cells after exposure
to native and modified forms of the lipoproteins. The effect of
lipoproteins and lipoproteins modified by oxidation or glycation on
prostacyclin production was measured in cultures of bovine aortic
endothelial cells (BAEC). LDL, and HDL2 and HDL3, within their
physiological concentration ranges, induced a significant increase in
PGI2 production by BAEC but with different timecourses and different
concentration-response curves. LDL-induced PGI2 production was
greater within the initial 4 hours of exposure than for HDL while
from 24 to 72 hours, the HDL-induced PGI2 production was greater than
for low density lipoprotein (LDL). LDL, within the initial 4 hours,
was more active at lower concentrations than HDL and the converse was
shown for HDL during the longer term incubations (24 to 72 hours).
PGI2 production induced by oxidized LDL was significantly greater
over 4 to 24 hours than native LDL but over longer incubations (48 to
72 hours) caused a comparative decrease in PGI2 production. Glycation
of LDL induced a significant increase in the lipoprotein-induced PGI2
production which persisted over 48 to 72 hours and which was greater
than the native form of the lipoprotein. Thus exposure of endothelial
cells to modified LDL increases PGI2 production in the short term (up
to 24 hours) but in longer term incubations (48 to 72 hours) causes
an inhibition of PGI2-producing capacity. Glycated HDL3 caused higher
production of PGI2 in the short term (4 to 24 hours) but reached
similar levels as HDL3 over time. Further experiments over many days
or even weeks need to be performed to demonstrate the long-term
deleterious effects of the modified lipoproteins. Glycation of HDL2
had no effect on the PGI2-producing capacity of the lipoprotein. Thus
modification of the lipoproteins can have significant effects on the
potential of the lipoproteins to induce PGI2 production in
macrovascular endothelial cells and this may have an influence on
vascular function in disease states such as diabetes and
atherosclerosis. While the changes appear to contradict data from
long-term in vivo studies, these results from in vitro studies may
reflect the situation in very early lesion development. Glycated LDL,
while causing an increase in endothelial cell PGI2 production, may be
involved in compromised endothelial function as glycated LDL is prone
to oxidation; oxidised LDL in our studies inhibited PGI2 production
by BAEC.
Received 12 January 1995; accepted in final form 15 May 1996.
APS Manuscript Number C28-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 June 96