In this article we have reviewed the evidence that implicates the organization and incorporation of mural thrombi as a significant component of atherosclerotic plaque growth in man. It has been emphasized that there is little or no evidence for a pathogenic role for thrombosis in plaque initiation or for the development of fatty streaks. We have suggested that the rapidly progressive category of atherosclerosis in man, as described by DeBakey, may well reflect a heightened propensity for mural or occlusive thrombosis in these patients. A broad spectrum of experimental studies examining the role of thrombosis in atherogenesis has been critically reviewed. These studies have established that experimental thrombi can become transformed into arterial fibrofatty plaques having many of the morphologic features of atherosclerosis. We have provided evidence, however, that the evolution of thrombi to fibrofatty lesions is dependent on the initial composition of the thrombi and that thrombi with a paucity of platelets and consisting predominantly of fibrin result only in fibrous intimal thickenings. The presence of hypercholesterolemia has been shown to influence the transformation of experimental thrombi. In particular, it slows the rate of thrombolysis, enhances the lipid content of the fibrofatty plaques, increases the numbers of macrophage-derived foam cells, and the frequency and extent of lesion calcification. Detailed lipid compositional studies of organizing thrombi in normolipidemic animals have shown that their lipid composition does not evolve toward the profile characteristic of atherosclerotic lesions and that the macrophage uptake of interstitial lipoproteins is probably a necessary component for the full biochemical development of the lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

This article has addressed the roles of the monocyte-macrophage in atherogenesis and factors influencing monocyte recruitment to the intima. The diversity of the secretory products of the macrophage and their putative participatory roles in pathogenesis have been reviewed and discussed. Additionally, we have presented summary data on the monocyte chemoattractant peptide SMC-CF and on the differentiation of the monocyte-derived foam cell. Discussion has centered on the concept of atherosclerosis as an inflammatory process.

Castanospermine, a plant alkaloid that inhibits the glycoprotein processing enzyme glucosidase I, has been used to inhibit N-linked oligosaccharide modification, resulting in the production of glycoproteins having Glc3Man7-9(GlcNAc)2 oligosaccharides. This alkaloid caused a significant inhibition of LDL endocytosis in cultured primate smooth muscle cells and human skin fibroblasts. At an optimum concentration of 250 micrograms/mL, castanospermine caused a 40% decrease in cell surface receptor-mediated LDL binding at 4 degrees C, with no apparent change in affinity. Further, the inhibitor had no direct effect on LDL metabolism. This inhibition of LDL receptor expression and function occurred only when the drug was present during de novo receptor synthesis, i.e., during up-regulation. Although the number of cell surface LDL receptors was significantly reduced in the presence of castanospermine, the total number of receptors in the cell was only slightly reduced, indicating that castanospermine induced a redistribution rather than a reduction in the number of receptors. Similarly, subcellular fractionation studies confirmed that castanospermine treatment of fibroblasts results in an altered distribution of receptor activity compared with controls. These findings are consistent with the conclusion that the decrease in specific LDL binding to cells grown in the presence of castanospermine is due to intracellular redistribution of the LDL receptor so that more receptor remains in internal compartments as a result of a diminished rate of transport.

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This synopsis emphasizes the inappropriateness of a "single stimulus-single response" approach in understanding the response of the arterial wall to injury and repair. The outcome of any injurious stimulus is a series of interactive cascades among the endogenousand exogenous cellular and non-cellular components of the arterial wall, and the cellular and non-cellular elements of the blood. Both genetic and hemodynamic factors can further influencethis response. The more prominent of the cellular and non-cellular components have beendiscussed.These include: I) the vascularendothelium, its dynamic interaction with macromolecules and formed elements of the blood, its role in the transport of plasma proteins, its influenceon the function of arterial smooth muscle cellsand the recruitment of blood-born monocytes; 2) the arterial smooth muscle cell, its role in the vasomotor function of the artery wall, arterial repair and reconstruction, metabolism of lipids and the secretion of cytokines regulating monocyte recruitment; 3) the mononuclear phagocyte, its role in arterial debridement, metabolism of modified LDLs, a precursor of the cholesteryl ester-rich foam cell, and the secretion of neutral hydrolases, bioactive lipids and cytokines; 4) lymphocytes, as mediators of the inflammatoryresponseand possibleautoimmune reactions;5)platelets, their rolesin hemostasis,thrombosis, atherogenesis, and the repair processand 6) plasma LDLs, their oxidative modification by cells of the vessel walland their roles in the injury process.The interactive processes among arterial and circulatingcomponents in both injury and repair is emphasized.