Metabolism of native and naturally occurring multiple modified low density lipoprotein in smooth muscle cells of human aortic intima.
The subfraction of low density lipoprotein (LDL) with low sialic acid content that caused accumulation of cholesterol esters in human aortic smooth muscle cells has been found in the blood of coronary atherosclerosis patients. It was demonstrated that this subfraction consists of LDL with small size, high electronegative charge, reduced lipid content, altered tertiary structure of apolipoprotein B, etc. LDL of this subfraction is naturally occurring multiple-modified LDL (nomLDL). In this study we compared the binding, uptake and proteolytic degradation of native LDL and nomLDL by smooth muscle cells cultured from human grossly normal intima, fatty streaks, and atherosclerotic plaques. Uptake of nomLDL by normal and atherosclerotic cells was 3.5- and 6-fold, respectively, higher than uptake of native LDL. Increased uptake of nomLDL was due to increased binding of this LDL by intimal smooth muscle cells. The enhanced binding is explained by the interaction of nomLDL with cellular receptors other than LDL-receptor. Modified LDL interacted with the scavenger receptor, asialoglycoprotein receptor, and also with cell surface proteoglycans. Rates of degradation of nomLDL were 1.5- and 5-fold lower than degradation of native LDL by normal and atherosclerotic cells, respectively. A low rate of nomLDL degradation was also demonstrated in homogenates of intimal cells. Activities of lysosomal proteinases of atherosclerotic cells were decreased compared with normal cells. Pepstatin A, a cathepsin D inhibitor, completely inhibited lipoprotein degradation, while serine, thiol, or metallo-proteinase inhibitors had partial effect. This fact reveals that cathepsin D is involved in initial stages of apoB degradation by intimal smooth muscle cells. Obtained data show that increased uptake and decreased lysosomal degradation of nomLDL may be the main cause of LDL accumulation in human aortic smooth muscle cells, leading to foam cell formation.
Tertov
V V
VV
Institute of Experimental Cardiology, Cardiology Research Center, Moscow, Russia.
Orekhov
A N
AN
D000328:Adult; D001011:Aorta / Q000378:metabolism*; D001055:Apolipoproteins B / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism; D001667:Binding, Competitive; D002478:Cells, Cultured; D002810:Chondroitinases and Chondroitin Lyases / Q000494:pharmacology; D004705:Endocytosis / Q000502:physiology; D005690:Galactose / Q000494:pharmacology; D019763:Heparin Lyase / Q000494:pharmacology; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D013997:Time Factors; D017539:Tunica Intima / Q000378:metabolism*; D000509:alpha-Fetoproteins / Q000494:pharmacology
D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D000509:alpha-Fetoproteins; D006821:Hyaluronoglucosaminidase; D002810:Chondroitinases and Chondroitin Lyases; D019763:Heparin Lyase; D005690:Galactose