Molecular interactions in human atherosclerotic plaques

Abstract

Most plasma proteins appear to be present in intima at concentrations that are a linear function of molecular weight and concentration in the plasma. Thus low density lipoprotein (LDL) (molecular weight, 2 X 10(6)) has the greatest retention relative to its plasma concentration, whereas the relative retention of albumin is only 15% of the relative retention of LDL. This gives rise to the concept that "whole plasma" crosses endothelium, and the steady state concentrations reflect rates of egress of the macromolecules, which in turn depend on molecular sieving. Fibrinogen is a major plasma protein in intima in addition to LDL and albumin, and there are also substantial amounts of the protease inhibitors alpha2-macroglobulin and alpha1-antitrypsin. Intima also contains insoluble derivatives of plasma--extracellular cholesterol, both free and esterified, and fibrin. The balances of intact LDL/"deposited" cholesterol and of fibrinogen/fibrin are closely linked with intimal morphology. Fibrinogen and electrophoretically mobile LDL are increased about threefold in gelatinous lesions, whereas there are only slight rises in fibrin and deposited cholesterol. In the deep layers of fibrous plaques, fibrin is increased fivefold and cholesterol up to thirtyfold. In these lipid-rich layers, LDL is rapidly lost on incubation of tissue samples, but in some gelatinous lesions it first increases and only decreases on longer incubation, suggesting release of a previously immobilized lipoprotein fraction. This immobilized lipoprotein was investigated by subjecting tissue samples to immunoelectrophoresis to remove mobile LDL and tissue enzymes, followed by treatment of the tissue with enzyme and measurement of the lipoprotein released on fresh immunoelectrophoresis plates. Plasmin or a crude collagenase released large amounts of lipoprotein from samples of amorphous atheroma lipid. For all samples the amount of lipoprotein released was highly correlated with the accumulation of deposited cholesterol, suggesting that immobilization of LDL may be an intermediate step in the irreversible deposition of extracellular cholesterol. Plasmin is highly effective in releasing immobilized lipoprotein, and the concentration of immobilized lipoprotein is significantly correlated with the concentration of insoluble fibrin, suggesting that the lipoprotein may in some way be immobilized by fibrin.