Inactivation of lysosomal proteases by oxidized low density lipoprotein is partially responsible for its poor degradation by mouse peritoneal macrophages.

Hoppe, George; O’Neil, June; Hoff, Hans

doi:10.1172/jci117490

Cited by 107 publications

(110 citation statements)

References 22 publications

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“…Highly ox-LDL appears therefore to transform macrophages into foam cells through several mechanisms, which include inhibition of cholesterol efflux 60 and inactivation of lysosomal proteases. 61 Our data thus suggest that progressive oxidation of LDL is associated with at least two distinct mechanisms of induction of foam cell formation. In summary, the current study demonstrates that LPL expression (enzyme activity and mRNA levels) is differentially modulated in human monocyte-derived macrophages by potentially atherogenic oxLDL that accumulates in the arterial wall.…”

Section: Time Course Of Evolution Of Oxidation Parameters and Phosphomentioning

confidence: 62%

Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

Stengel

Antonucci

Gaoua

et al. 1998

ATVB

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Abstract-The regulation of macrophage lipoprotein lipase (LPL) secretion and mRNA expression by atherogenic lipoproteins is of critical relevance to foam cell formation. LPL is present in arterial lesions and constitutes a bridging ligand between lipoproteins, proteoglycans, and cell receptors, thus favoring macrophage lipoprotein uptake and lipid accumulation. We investigated the effects of native and of oxidized lipoproteins on the expression of LPL in an in vitro human monocyte-macrophage system. Exposure of mature macrophages (day 12) to highly copper-oxidized human low density lipoprotein (LDL) (100 g protein per milliliter) led to marked reduction in the expression of LPL activity (Ϫ62%, PϽ0.01) and mRNA level (Ϫ47%, PϽ0.05); native LDL, acetylated LDL, and LDL oxidized for Ͻ6 hours were without effect. The reduction in LPL activity became significant at a threshold of 6 hours of LDL oxidation (Ϫ31%, PϽ0.05). Among the biologically active sterols formed during LDL oxidation, only 7␤-hydroxycholesterol (5 g/mL) induced a minor reduction in macrophage LPL activity, whereas 25-hydroxycholesterol was without effect. By contrast, lysophosphatidylcholine, whose LDL content increased in parallel with the degree of oxidation, induced significant reductions in LPL activity and mRNA levels at concentrations of 2 to 20 mol/L (Ϫ34% to Ϫ53%, PϽ0.01).Our results demonstrate that highly oxidized LDL (Ͼ6-hour oxidation) exerts negative feedback on LPL secretion in human monocytes-macrophages via a reduction in mRNA levels. By contrast, native LDL and mildly oxidized LDL (Ͻ6-hour oxidation) did not exert a feedback effect on LPL expression. We speculate that the content of lysophosphatidylcholine and, to a lesser degree, of 7␤-hydroxycholesterol in oxidized LDLs is responsible for the downregulation of LPL activity and mRNA abundance in human monocyte-derived macrophages and may therefore modulate LPL-mediated pathways of lipoprotein uptake during conversion of macrophages to foam cells. 2-5The mechanism of the conversion of macrophages to foam cells containing large amounts of cholesterol, cholesteryl esters, and TGs is presently the subject of extensive investigation. 6 The uptake of lipoproteins by such cells involves several receptors of distinct specificity, including scavenger receptors, 7 CD36, 8 and Fc receptors 9 for oxLDL; the LDL receptor; the LDL receptor-related protein receptor 10,11 ; the VLDL receptor for TG-rich lipoproteins 12 ; and last, membrane-binding proteins for uptake of certain TG-rich lipoproteins. 13 These cellular uptake mechanisms are rendered complex by the contribution of additional factors such as heparan sulfate proteoglycans of the matrix and cell plasma membranes and equally by LPL, 14 which may serve to "anchor" lipoproteins to the cell surface.LPL is a key enzyme of lipoprotein metabolism that hydrolyzes the TG component of chylomicrons and VLDL. 15 Moreover, LPL can act as a ligand to create a "bridge" between TG-rich lipoproteins and several receptors of the LDL family.16 LPL may al...

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Section: Time Course Of Evolution Of Oxidation Parameters and Phosphomentioning

confidence: 62%

Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

Stengel

Antonucci

Gaoua

et al. 1998

ATVB

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“…We have shown previously (64) that ox-LDL is poorly degraded and accumulates in lysosomes, due in part to resistance of ox-LDL to cathepsins. However, Hoff and colleagues (65,66) demonstrated that reactive aldehydes in ox-LDL can directly inactivate cathepsins, and it seems likely that such reactive components of ox-LDL could also inhibit lysosomal acid sphingomyelinase. It has been reported that 7-ketocholesterol in ox-LDL results in the inhibition of lysosomal sphingomyelinase (67).…”

Section: Discussionmentioning

confidence: 99%

Oxidized Low Density Lipoprotein Inhibits Macrophage Apoptosis by Blocking Ceramide Generation, Thereby Maintaining Protein Kinase B Activation and Bcl-XL Levels

Hundal¹,

Gómez-Muñoz²,

Kong³

et al. 2003

Journal of Biological Chemistry

103

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Macrophages play a central role in the development and progression of atherosclerotic lesions. It is well known that oxidized low density lipoprotein (ox-LDL) promotes the recruitment of monocytes (which differentiate to macrophages) into the intima. We reported recently that ox-LDL blocks apoptosis in bone marrow-derived macrophages deprived of macrophage colonystimulating factor (M-CSF) by a mechanism involving protein kinase B (PKB) (Hundal, R., Salh, B., Schrader, J., Gó mez-Muñ oz, A., Duronio, V., and Steinbrecher, U. (2001) J. Lipid Res. 42, 1483-1491). The aims of the present study were 1) to define the apoptotic pathway involved in the pro-survival effect of ox-LDL; 2) to determine which PKB target mediated this effect; and 3) to identify mechanisms responsible for PKB activation by ox-LDL. Apoptosis following M-CSF withdrawal was accompanied by activation of the caspase 9-caspase 3 cascade and cytochrome c release from mitochondria, but the caspase 8 pathway was unaffected. M-CSF withdrawal resulted in a marked and selective reduction in Bcl-X L protein and mRNA levels, and this decrease was prevented by ox-LDL. The ability of ox-LDL to preserve Bcl-X L levels was blocked by NFB antagonists, thereby implicating IB kinase as a key PKB target. M-CSF deprivation resulted in activation of acid sphingomyelinase and an increase in ceramide levels. Desipramine (a sphingomyelinase inhibitor) prevented the increase in ceramide and inhibited apoptosis after M-CSF deprivation. Ox-LDL completely blocked the increase in acid sphingomyelinase activity as well as the increase in ceramide after M-CSF deprivation. Pretreatment of macrophages with C 2 -ceramide reversed the effect of ox-LDL on PKB and macrophage survival. These results indicate that ox-LDL prevents apoptosis in M-CSFdeprived macrophages at least in part by inhibiting acid sphingomyelinase. This in turn prevents ceramide-induced down-regulation of PKB, the activity of which is required to maintain production of Bcl-X L .

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“…13,16,25,31,32 In this study, a ball homogenizer was used, which, in combination with the estimation of lysosomal marker enzyme activity, permitted us to identify alterations in lysosomal membrane stability and enzyme inactivation in a simple and efficient way on a limited number of cells.…”

Section: Discussionmentioning

confidence: 99%

“…This is in contrast to the fate of nLDL or AcLDL, which are easily degraded by lysosomal enzymes without leaving any undegradable material. [13][14][15][16] Studies in cellular and cell-free model systems have shown that oxLDL seems to inactivate lysosomal proteases, although the mechanisms involved are still not well understood. 14 -16 A better knowledge of that process would certainly be helpful in the elucidation of the mechanisms behind foam cell formation and atherogenesis.…”

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confidence: 99%

Uptake of Oxidized LDL by Macrophages Results in Partial Lysosomal Enzyme Inactivation and Relocation

Yuan

Olsson

et al. 1998

ATVB

109

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Abstract-The cytotoxicity of oxidized LDL (oxLDL) to several types of artery wall cells might contribute to atherosclerosis by causing cell death, presumably by both apoptosis and necrosis. After its uptake into macrophage lysosomes by receptor-mediated endocytosis, oxLDL is poorly degraded, resulting in ceroid-containing foam cells. We studied the influence of oxLDL on lysosomal enzyme activity and, in particular, on lysosomal membrane stability and the modulation of these cellular characteristics by HDL and vitamin E (vit-E). Unexposed cells and cells exposed to acetylated LDL (AcLDL) were used as controls. The lysosomal marker enzymes cathepsin L and N-acetyl-␤-glucosaminidase (NA␤Gase) were biochemically assayed in J-774 cells after fractionation. Lysosomal integrity in living cells was assayed by the acridine orange (AO) relocation test. Cathepsin D was immunocytochemically demonstrated in J-774 cells and human monocyte-derived macrophages. We found that the total activities of NA␤Gase and cathepsin L were significantly decreased, whereas their relative cytosolic activities were enhanced, after oxLDL exposure. Labilization of the lysosomal membranes was further proven by decreased lysosomal AO uptake and relocation to the cytosol of cathepsin D, as estimated by light and electron microscopic immunocytochemistry. HDL and vit-E diminished the cytotoxicity of oxLDL by decreasing the lysosomal damage. The results indicate that endocytosed oxLDL not only partially inactivates lysosomal enzymes but also destabilizes the acidic vacuolar compartment, causing relocation of lysosomal enzymes to the cytosol. Exposure to AcLDL resulted in its uptake with enlargement of the lysosomal apparatus, but the stability of the lysosomal membranes was not changed. (Arterioscler Thromb Vasc Biol. 1998;18:177-184.)

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Inactivation of lysosomal proteases by oxidized low density lipoprotein is partially responsible for its poor degradation by mouse peritoneal macrophages.

Cited by 107 publications

References 22 publications

Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

Oxidized Low Density Lipoprotein Inhibits Macrophage Apoptosis by Blocking Ceramide Generation, Thereby Maintaining Protein Kinase B Activation and Bcl-XL Levels

Uptake of Oxidized LDL by Macrophages Results in Partial Lysosomal Enzyme Inactivation and Relocation

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