Biomaterial Database

Oxidized low density lipoprotein reduces thrombomodulin transcription in cultured human endothelial cells through degradation of the lipoprotein in lysosomes. 1996

H Ishii, and K Kizaki, and S Horie, and M Kazama

Department of Clinical Biochemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Tsukui, Kanagawa 199-01, Japan.

Oxidized low density lipoprotein (LDL), a potent atherogenic lipoprotein, has been shown to cause the alteration of various endothelial functions. We have examined the effect of oxidized LDL on the cofactor activity for thrombin-dependent protein C activation and expression of thrombomodulin (TM), a cell surface antithrombotic glycoprotein, on cultured human umbilical vein endothelial cells. Oxidized LDL prepared by irradiation of LDL with 254-nm ultraviolet light did not directly affect the cofactor activity of isolated TM. Exposure of the cells to oxidized LDL (25-200 microg/ml), but not native LDL and acetylated LDL, reduced TM cofactor activity in parallel with its antigen levels on the cell surface in an oxidation-, concentration- and time-dependent manner. TM mRNA levels were reduced prior to decrease in TM antigen levels and were 50% of the control levels at 3.0 h after treatment of the cells with oxidized LDL. The apparent half-life time (t1/2 = 2.8 h) of TM mRNA in the oxidized LDL-treated cells, however, did not significantly differ from that (t1/2 = 2.6 h) in the control cells when the cells were coincubated with 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, a transcriptional inhibitor. Treatment of the cells with bafilomycin A1, an inhibitor for the proton pump of the lysosomes, inhibited intracellular degradation of the LDL and prevented down-regulations of the mRNA and the cell surface TM antigen levels caused by oxidized LDL. The inhibitor molecule in oxidized LDL was shown to be a lipid; organic solvent extracts (300 mg/ml cholesterol, an equivalent concentration with lipids in 200 microg/ml oxidized LDL) of oxidized LDL inhibited expression of TM antigen to nearly the same extent as the oxidized LDL, although water extracts did not affect TM expression on the cells. These results suggested that down-regulation of TM on endothelial cells exposed to oxidized LDL resulted from inhibition of its transcription mediated by lysosomal degradation of oxidized LDL and that a lipid component in the LDL could be an active species. A decrease in TM expression on the surface of endothelial cells may contribute to promote thrombosis in atherosclerotic lesions.

UI	MeSH Term	Description	Entries
D008074	Lipoproteins	Lipid-protein complexes involved in the transportation and metabolism of lipids in the body. They are spherical particles consisting of a hydrophobic core of TRIGLYCERIDES and CHOLESTEROL ESTERS surrounded by a layer of hydrophilic free CHOLESTEROL; PHOSPHOLIPIDS; and APOLIPOPROTEINS. Lipoproteins are classified by their varying buoyant density and sizes.	Circulating Lipoproteins,Lipoprotein,Lipoproteins, Circulating
D008077	Lipoproteins, LDL	A class of lipoproteins of small size (18-25 nm) and light (1.019-1.063 g/ml) particles with a core composed mainly of CHOLESTEROL ESTERS and smaller amounts of TRIGLYCERIDES. The surface monolayer consists mostly of PHOSPHOLIPIDS, a single copy of APOLIPOPROTEIN B-100, and free cholesterol molecules. The main LDL function is to transport cholesterol and cholesterol esters to extrahepatic tissues.	Low-Density Lipoprotein,Low-Density Lipoproteins,beta-Lipoprotein,beta-Lipoproteins,LDL(1),LDL(2),LDL-1,LDL-2,LDL1,LDL2,Low-Density Lipoprotein 1,Low-Density Lipoprotein 2,LDL Lipoproteins,Lipoprotein, Low-Density,Lipoproteins, Low-Density,Low Density Lipoprotein,Low Density Lipoprotein 1,Low Density Lipoprotein 2,Low Density Lipoproteins,beta Lipoprotein,beta Lipoproteins
D008247	Lysosomes	A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes MEMBRANE FUSION. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed).	Autolysosome,Autolysosomes,Lysosome
D010084	Oxidation-Reduction	A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471).	Redox,Oxidation Reduction
D004730	Endothelium, Vascular	Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components.	Capillary Endothelium,Vascular Endothelium,Capillary Endotheliums,Endothelium, Capillary,Endotheliums, Capillary,Endotheliums, Vascular,Vascular Endotheliums
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006180	Proton-Translocating ATPases	Multisubunit enzymes that reversibly synthesize ADENOSINE TRIPHOSPHATE. They are coupled to the transport of protons across a membrane.	ATP Dependent Proton Translocase,ATPase, F0,ATPase, F1,Adenosinetriphosphatase F1,F(1)F(0)-ATPase,F1 ATPase,H(+)-Transporting ATP Synthase,H(+)-Transporting ATPase,H(+)ATPase Complex,Proton-Translocating ATPase,Proton-Translocating ATPase Complex,Proton-Translocating ATPase Complexes,ATPase, F(1)F(0),ATPase, F0F1,ATPase, H(+),Adenosine Triphosphatase Complex,F(0)F(1)-ATP Synthase,F-0-ATPase,F-1-ATPase,F0F1 ATPase,F1-ATPase,F1F0 ATPase Complex,H(+)-ATPase,H(+)-Transporting ATP Synthase, Acyl-Phosphate-Linked,H+ ATPase,H+ Transporting ATP Synthase,H+-Translocating ATPase,Proton-Translocating ATPase, F0 Sector,Proton-Translocating ATPase, F1 Sector,ATPase Complex, Proton-Translocating,ATPase Complexes, Proton-Translocating,ATPase, H+,ATPase, H+-Translocating,ATPase, Proton-Translocating,Complex, Adenosine Triphosphatase,Complexes, Proton-Translocating ATPase,F 0 ATPase,F 1 ATPase,F0 ATPase,H+ Translocating ATPase,Proton Translocating ATPase,Proton Translocating ATPase Complex,Proton Translocating ATPase Complexes,Proton Translocating ATPase, F0 Sector,Proton Translocating ATPase, F1 Sector,Triphosphatase Complex, Adenosine
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006863	Hydrogen-Ion Concentration	The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH	pH,Concentration, Hydrogen-Ion,Concentrations, Hydrogen-Ion,Hydrogen Ion Concentration,Hydrogen-Ion Concentrations
D000900	Anti-Bacterial Agents	Substances that inhibit the growth or reproduction of BACTERIA.	Anti-Bacterial Agent,Anti-Bacterial Compound,Anti-Mycobacterial Agent,Antibacterial Agent,Antibiotics,Antimycobacterial Agent,Bacteriocidal Agent,Bacteriocide,Anti-Bacterial Compounds,Anti-Mycobacterial Agents,Antibacterial Agents,Antibiotic,Antimycobacterial Agents,Bacteriocidal Agents,Bacteriocides,Agent, Anti-Bacterial,Agent, Anti-Mycobacterial,Agent, Antibacterial,Agent, Antimycobacterial,Agent, Bacteriocidal,Agents, Anti-Bacterial,Agents, Anti-Mycobacterial,Agents, Antibacterial,Agents, Antimycobacterial,Agents, Bacteriocidal,Anti Bacterial Agent,Anti Bacterial Agents,Anti Bacterial Compound,Anti Bacterial Compounds,Anti Mycobacterial Agent,Anti Mycobacterial Agents,Compound, Anti-Bacterial,Compounds, Anti-Bacterial