M. Naruszewicz et al., THIOLATION OF LOW-DENSITY-LIPOPROTEIN BY HOMOCYSTEINE THIOLACTONE CAUSES INCREASED AGGREGATION AND ALTERED INTERACTION WITH CULTURED MACROPHAGES, NMCD. Nutrition Metabolism and Cardiovascular Diseases, 4(2), 1994, pp. 70-77
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.