Lipoproteins and the inhibitory effect of human endothelial cells on platelet function.

Abstract

SUMMARY We investigated the effect of plasma low density lipoproteins (LDL), very low density lipoproteins (VLDL), and high density lipoproteins (HDL) on the platelet inhibitory effect of primary cultures of human endothelial cell monolayers (ECM). ECM incubated with lipoprotein-deficient plasma (LDP) for 2 hours at 37°C had an inhibitory effect on ADP-and collagen-induced platelet aggregation and prostaglandin production in platelet-rich plasma similar to that observed when ECM were preincubated with growth medium or plasma. Concentrations of LDL in LDP up to a protein concentration of 1600 pg/ml had an inhibitory effect on the endothelial cells' ability to modulate these platelet reactions. VLDL at the highest concentration (1600 jug/ml) had a slightly inhibitory effect, whereas HDL showed no such effect. The inhibitory effect of LDL was not observed during the first hour of incubation. When HDL in concentrations similar to or higher than LDL were combined with LDL, the inhibitory effect of LDL was partially reduced. VLDL combined with LDL or HDL did not interfere with the effects of the later fractions. The inhibitory effect of LDL was significantly reduced when LDL were diluted in whole plasma. Prostacyclin which is synthesized and released from the endothelial cells and contributes to the inhibitory effect upon platelets did not change its effect on platelet reactivity by preincubation with the various lipoprotein fractions. The current studies may indicate that LDL have a direct effect on the endothelial cells and that this effect may be partially counteracted by HDL. This effect of LDL on the endothelial cells reduces the endothelium's ability to inhibit platelet aggregation and thus could favor the tendency to thrombus formation.RECENT studies have shown that microsomal fractions of the vessel wall lining of arteries and veins are able to generate prostacyclin (PGI 2 ) from prostaglandin endoperoxides and arachidonic acid. 1 PGI 2 has a strong inhibitory effect on platelet aggregation induced by collagen, ADP, and epinephrine. It has been shown further that human endothelial cells grown in culture spontaneously release a platelet antiaggregatory principle that also inhibits malondialdehyde (MDA) production in platelets induced by collagen. 2 ' 3 These observations suggest that a normally functioning endothelial cell is able to counteract platelet aggregation and thrombus formation, and that this effect is caused partially by PGI2 4 through an inhibition of thromboxane A 2 (TXA 2 ) generation in platelets, which is the strongest naturally occurring platelet-aggregating compound described. 5 Epidemiological studies have shown a positive correlation between the plasma concentration of

Eighth Gaddum Memorial Lecture University of London Institute of Education December 1980: Biological Importance of Prostacyclin

“…Nordoy, Svensson, Wiebe & Hoak (1978) were the first to show that LDL reduced the release of a prostacyclin-like substance by human endothelial cells. Beitz & Forster (1980) extended these observations by showing that LDL inhibited whereas HDL stimulated prostacyclin synthesis.…”

Prostacyclin production by endothelial cells. Effects of sera from normal and hyperlipidemic subjects.

“…45 In other studies, incubation of human umbilical cord endothelial cells (HUEC) with low density lipoproteins diminished PGI 2 production, 6 but this effect may have reflected oxidation of LDL during isolation. 7 Since endothelial cells in vivo are not exposed to isolated lipoprotein fractions, and little information is available on the effect of hyperlipidemic sera on PGI 2 production by endothelial cells, the influence of different serum lipoprotein patterns on PGI 2 formation by cells requires further examination.…”

“…10 - 11 Isolated, activated platelets release nondialyzable substances that enhance PGI 2 formation by porcine endothelial cells. 6 In addition, a dialyzable PGI 2 -stimulating factor is formed during the activation of the intrinsic pathway of blood coagulation. 12 These reports suggest the existence of at least two separate serum factors with PGI 2 stimulating activity.…”

“…The concomitant presence of the different lipoprotein classes, as in serum, both at normal and pathological concentrations, might result in reduction or even reversal of their individual effects. 6 Two possible interpretations of these observations may be made: 1) donation to confluent endothelial cells of arachidonic acid carried by separated HDL is not the major determinant of the stimulatory effect of whole serum; or 2) moderate levels of HDL are sufficient for maximal stimulation even in the presence of high LDL. The effects of sera with elevated HDL levels were not tested in these experiments.…”

Biology and therapeutic potential of prostacyclin.

“…' 98 Nordoy and co-workers 99 were the first to show that LDL reduced the release of a prostacyclinlike substance by human endothelial cells. Beitz and Forster 100 extended these observations by showing that LDL inhibited, whereas HDL stimulated prostacyclin synthesis.…”