Low-density lipoproteins (LDL) have been shown to cause aggregation of human blood platelets at concentrations above 2 g of protein/l. The secretion of the contents of platelet dense granules was detected, but not that of the lysosomes. LDL gave rise to a mobilization of [3H]arachidonic acid from phospholipids and the appearance of products of the cyclo-oxygenase pathway after only 10 s. LDL-promoted aggregation was inhibited by both aspirin and indomethacin. There was an increase in 3H-labelled diacylglycerols and the phosphorylation of 47 kDa proteins. LDL therefore shares at least some of the mechanisms of stimulus/response coupling with those of other agonists.

The atherosclerotic properties of low-density lipoproteins (LDL) are thought to be strongly enhanced by oxidation. The lipid-lowering drug probucol reduces the susceptibility of LDL to oxidation. Synchrotron X-ray and high-flux neutron solution scattering curves were used to characterise the structural properties of human LDL, before and after modification by oxidation with CuZt and the addition of probucol, in order to evaluate these techniques. Analyses based on Guinier plots, simple two-shell spherical modelling, and the use of cubic splines and indirect transformation show that a 20-h incubation with Cu2+ ions (but not 6 h) causes some of the LDL to associate to form larger aggregated particles. Gel electrophoresis on Cu2+-oxidised LDL shows a concomitant degradation of the apolipoprotein B-100 as well as the formation of high molecular mass forms. These experiments indicate that the apoprotein B-100 structure has been significantly disrupted by oxidation. The addition of probucol to LDL causes an increase in the polydispersity of LDL, as evidenced by small changes in the Guinier curves and some weakening of the minima in the X-ray scattering curves. N o changes in the quasispherical shape of LDL are observed and gel electrophoresis indicates no changes. It is possible that probucol may exert its effect by increasing the range of sizes of LDL and that the lipid-lowering effect of probucol in vivo might be caused by the preferential catabolism of the higher molecular mass forms of LDL thus created.Cardiovascular disease is implicated in half of all deaths in industrialised countries. Epidemiological studies show a strong positive correlation between elevated plasma concentrations of low-density lipoproteins (LDL) cholesterol and the risk of premature coronary heart disease [l, 21. The role of LDL is to deliver cholesterol to body tissues which require it for membrane synthesis and steroid hormone production [3]. LDL is distinguishable from all other lipoprotein classes in plasma by its high relative proportion of cholesteryl ester and the presence of a single apolipoprotein (apo) B-100. LDL has a simple quasi-spherical particle symmetry of outer diameter 21 -25 nm, as determined by electron microscopy and solution scattering [4 -81. It is composed of one molecule of apo B-100 with a 4% (by mass) oligosaccharide content (Table 1) and its binding to lipid can be likened to its insertion into a lipid vesicle [8 -121. Compositional studies show that LDL is 77% (by mass) lipid. There are about 2900 lipid molecules (Table l), primarily cholesteryl linoleate and triacylglycerol in the core, surrounded by a monolayer of polar phospholipids and cholesterol. Secondary structure predictions, circular dichroism and Fourier-transform infrared (FT-IR) spectroscopy show that apo B-100 is approximately 40% cc-helix, 25% fl-sheet and 35% random coil in its main chain conformation [9, 11, 13 - B-100 are found at the N-terminus, this part is presumed to constitute a globular structure.The presence of lipid-laden foam cells is a...

We have shown previously that corpus luteum cells isolated from the superovulated ovaries of rats treated with 4-amino-pyrazolo[3,4-d]pyrimidine constitute a suitable experimental system by which to investigate the mechanism in which plasma high-density lipoprotein (HDL) plays a role in luteal cellular progesterone synthesis. In the present study, the rate of luteal cellular progesterone synthesis was shown to be stimulated by '"I-labelled HDL up to about 70% of the rate achieved in the presence of native HDL. The concentration of HDL needed for half-maximal stimulation of progesterone synthesis in the presence of lutropin was not significantly different irrespective of whether radioiodinated HDL or unlabelled HDL was used. Experimental conditions for studying the binding of 1251-labelled HDL to isolated luteal cells have been defined and cellular binding affinity and binding capacity have been measured. Exposure of the luteal cells to pronase virtually abolished their capacity to bind lZ51-HDL and made them unable to respond to added HDL by increasing their rate of progesterone synthesis in the presence of lutropin. Control experiments showed this effect of pronase on cellular progesterone synthesis not to be due to destruction of cellular lutropin receptors, nor to general cellular damage. This evidence supports the view that luteal cellular binding of HDL is part of the mechanism by which HDL acts in luteal progesterone synthesis. Cellular binding capacity and affinity for 1251-labelled HDL were the same irrespective of whether or not lutropin was present during incubation. Furthermore, the binding capacity and affinity of cells from the ovaries of rats not treated with 4-amino-pyrazolo[3,4-d]pyrimidine were the same as in luteal cells isolated from rats that had been treated.The work described in this paper is relevant to the mechanism by which high-density lipoprotein (HDL) acts in progesterone synthesis by the corpus luteum of the rat ovary. Using a preparation of isolated rat corpus luteum cells [l], we have already obtained and presented evidence that HDL plays such a role [2]. Briefly, we found that progesterone synthesis was very much impaired in corpus luteum cells isolated from rats which had been treated beforehand with 4-aminopyrazolo[3,4-d]pyrimidine (4-APP), a treatment which essentially deprives their tissues of access to circulating lipoproteins [2]. Rat HDL, but not other rat plasma lipoproteins, when added to the cell incubation medium, restored progesterone synthesis by these cells to normal levels [2]. Progesterone synthesis by corpus luteum cells isolated from rats which had not been treated with 4-APP was not significantly affected by added HDL [2]. Since deprivation of access to lipoproteins in vivo caused a defect in corpus luteum cell progesterone synthesis which was reversible by HDL presented in vitra, we concluded that HDL is necessary for luteal progesterone synthesis in the rat [2].

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