Promotes Foam Cell Formation Research Articles

Induction of interleukin 1 beta expression from human peripheral blood monocyte-derived macrophages by 9-hydroxyoctadecadienoic acid.

Oxidatively modified low density lipoproteins (LDL) have recently been proposed to play a role in atherogenesis by promoting foam cell formation and endothelial cell toxicity. The purpose of the present study was to determine whether modified LDL could also induce macrophage release of interleukin 1 beta (IL-1 beta), a cytokine which enhances vascular smooth muscle cell proliferation, another feature of the atherosclerotic process. LDL were oxidatively modified by incubation with either Cu2+ (Cu(2+)-LDL) or human peripheral blood monocyte-derived macrophages (M-LDL). Incubation of these modified LDL with macrophages (6 x 10(6) cells/culture) resulted in a dose-dependent induction of IL-1 beta release. At 300 micrograms protein/ml, Cu(2+)-LDL and M-LDL induced 422 and 333 pg of IL-1 beta/culture, respectively. Saponified Cu(2+)-LDL and M-LDL were shown to contain 9- and 13-hydroxyoctadecadienoic acid (HODE), lipid oxidation products of linoleate. When tested for activity in macrophage culture (3 x 10(6) cells/culture), it was found that 9-HODE and 13-HODE (final concentration 33 microM) induced the release of 122 and 43 pg of IL-1 beta/culture, respectively, whereas untreated cells released only 4 pg of IL-1 beta/culture. Incubation of macrophages with cholesteryl-9-HODE also induced IL-1 beta release; however, the degree of induction of IL-1 beta release by 9-HODE or its cholesteryl ester relative to modified LDL suggests that other components in oxidized LDL may also contribute to IL-1 beta induction. 9-HODE was rapidly taken up by macrophages, and the kinetics were similar to IL-1 beta release. A 1.5- to 6-fold increase in the level of IL-1 beta mRNA was detected as little as 3-h post-9-HODE treatment. The induction of IL-1 beta release from human monocyte-derived macrophages by 9-HODE and cholesteryl-9-HODE suggests a role for modified LDL, and its associated linoleate oxidation products, in vascular smooth muscle cell proliferation.

Proteoglycans produced by cholesterol-enriched macrophages bind plasma low density lipoprotein

Proteoglycans (PG) produced by [ 35S]sulfate and [ 3H]serine labeled cultures of cholesterol-enriched macrophages obtained from atherosclerosis-susceptible White Carneau (WC) and -resistant Show Racer (SR) pigeons were characterized and assessed for their capacity to bind low density lipoprotein (LDL). The majority of 35S-labeled PG was released into the culture media in both WC and SR macrophage cultures and consisted of large and small size PG as determined by Sepharose CL-4B chromatography. Large PG were identified as chondroitin sulfate-PG comprised of 4-sulfated disaccharides whereas small PG consisted of primarily 4-sulfated chondroitin sulfate-PG and lesser amounts of heparin sulfate-PG. Experiments demonstrated that 32–34% of 35S-labeled large PG and 86–93% of small PG bound to LDL-substituted Sepharose. Interactions between PG and LDL-substituted Sepharose were inhibited in the presence of heparin or soluble LDL. Glycosaminoglycans derived from macrophage PG had a decreased binding affinity demonstrating the importance of an intact PG. The results suggest that macrophage PG may facilitate trapping of LDL in the intimal intima and promote foam cell formation through a mechanism involving the uptake of PG-LDL complexes.

ApoE-3-specific metabolism of human plasma very low density lipoproteins in cultured J-774 macrophages.

The effect of apoprotein E on the cellular metabolism of very low density lipoproteins (VLDL) was studied using the J-774 macrophage-like cell line as a foam cell model. Exogenous (plasmatic and recombinant) apoE-3 caused a marked enhancement of the cellular binding, association, and degradation of VLDL fractions I, II, and III from both normolipidemic and hypertriglyceridemic subjects. ApoE-3 did not affect the cellular metabolism of low density lipoproteins (LDL). The stimulatory effect of apoE-3 was specific and was not observed with E-2. ApoE-mediated enhancement of VLDL metabolism was markedly suppressed by competition with LDL or by down-regulation of the LDL receptor while the basal cellular metabolism of VLDL was not. The macrophage, however, appears also to exhibit a second apoE-3-dependent pathway for VLDL metabolism which is discerned from the LDL and scavenger receptors and is relatively resistant to cholesterol in the culture medium. This pathway is responsible for the basal and perhaps a small fraction of the apoE-3-stimulated metabolism of VLDL in the macrophage. Such activity may play a role in promoting foam cell formation by triglyceride-rich lipoproteins.