THIOLATION OF LOW-DENSITY-LIPOPROTEIN BY HOMOCYSTEINE THIOLACTONE CAUSES INCREASED AGGREGATION AND ALTERED INTERACTION WITH CULTURED MACROPHAGES

Because of the importance of low-density lipoproteins (LDL) and homocy steine in atherogenesis, modification of the chemical and biological p roperties of human LDL was studied by thiolation of LDL with the cycli c internal lactone, homocysteine thiolactone. Thiolated LDL was found to become aggregated and susceptible to spontaneous precipitation beca use of interaction between homocysteinyl groups attached by peptide bo nds to the lysyl epsilon amino groups of apolipoprotein B. Thiolation was found to increase internalization of LDL by membrane receptors and by phagocytosis, degradation, and cholesterol accumulation within cul tured human monocyte-derived macrophages. Degradation of thiolated LDL by macrophages was found to be inhibited by cytochalasin B, an inhibi tor of phagocytosis, and thiolated LDL-gold aggregates were observed i n phagolysosomes of cultured macrophages by electron microscopy. Thiol ation of LDL was found to decrease binding of LDL to the BE receptors of normal human fibroblasts. Thiolation of LDL by homocysteine thiolac tone did not increase susceptibility of LDL to oxidation by CUSO4 in v itro. Formation of thiolated LDL may explain in part the pathophysiolo gical process by which homocysteine accumulation causes intimal injury and deposition of cholesterol within atherosclerotic plaques.