PMA activation of macrophages alters macrophage metabolism of aggregated LDL
Aggregation of LDL may contribute to its retention in atherosclerotic lesions. Previously, we showed that aggregated LDL induces and enters surface-connected compartments (SCCs) in human monocyte-derived macrophages by a process we have named patocytosis. Aggregated LDL was disaggregated and release...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2002-08-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520300596 |
| _version_ | 1818740256842711040 |
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| author | Wei Huang Itsuko Ishii Wei-Yang Zhang Miyahiko Sonobe Howard S. Kruth |
| author_facet | Wei Huang Itsuko Ishii Wei-Yang Zhang Miyahiko Sonobe Howard S. Kruth |
| author_sort | Wei Huang |
| collection | DOAJ |
| description | Aggregation of LDL may contribute to its retention in atherosclerotic lesions. Previously, we showed that aggregated LDL induces and enters surface-connected compartments (SCCs) in human monocyte-derived macrophages by a process we have named patocytosis. Aggregated LDL was disaggregated and released from SCCs of macrophages when exposed to human lipoprotein-deficient serum. The serum factor that mediated aggregated LDL release and disaggregation was plasmin generated from plasminogen by macrophage urokinase plasminogen activator. We now show that activation of macrophages with PMA inhibits plasmin-mediated release of aggregated LDL from macrophages. With macrophage activation, plasminogen released about 60% less cholesterol and 63% less TCA-insoluble 125I-aggregated LDL than when macrophages were not activated. Electron microscopy showed that PMA did not cause SCCs to close, which could have trapped aggregated LDL within the SCCs and limited protease access to aggregated LDL. Rather, PMA decreased macrophage generation of plasmin by 61%, and stimulated lysosomal degradation of aggregated LDL by more than 2-fold. Degradation was mediated by protein kinase C, shown by the finding that degradation was inhibited by the protein kinase C inhibitor Gö6976. PMA-stimulated degradation of aggregated LDL was associated with a 3-fold increase in cholesterol esterification, consistent with hydrolysis and re-esterification of aggregated LDL-derived cholesteryl ester.In conclusion, macrophage activation with PMA causes more of the aggregated LDL that enters macrophage SCCs to be metabolized by lysosomes. This results in more cholesterol to be stored in macrophages and less aggregated LDL to be available for plasmin-mediated release from macrophage SCCs. |
| first_indexed | 2024-12-18T01:37:51Z |
| format | Article |
| id | doaj.art-99e25cc2b6624babbea30c07026809c8 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-18T01:37:51Z |
| publishDate | 2002-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-99e25cc2b6624babbea30c07026809c82022-12-21T21:25:25ZengElsevierJournal of Lipid Research0022-22752002-08-0143812751282PMA activation of macrophages alters macrophage metabolism of aggregated LDLWei Huang0Itsuko Ishii1Wei-Yang Zhang2Miyahiko Sonobe3Howard S. Kruth4Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 5N-113, 10 Center Drive MSC 1422, Bethesda, MD 20892Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 5N-113, 10 Center Drive MSC 1422, Bethesda, MD 20892Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 5N-113, 10 Center Drive MSC 1422, Bethesda, MD 20892Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 5N-113, 10 Center Drive MSC 1422, Bethesda, MD 20892To whom correspondence should be addressed.; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 5N-113, 10 Center Drive MSC 1422, Bethesda, MD 20892Aggregation of LDL may contribute to its retention in atherosclerotic lesions. Previously, we showed that aggregated LDL induces and enters surface-connected compartments (SCCs) in human monocyte-derived macrophages by a process we have named patocytosis. Aggregated LDL was disaggregated and released from SCCs of macrophages when exposed to human lipoprotein-deficient serum. The serum factor that mediated aggregated LDL release and disaggregation was plasmin generated from plasminogen by macrophage urokinase plasminogen activator. We now show that activation of macrophages with PMA inhibits plasmin-mediated release of aggregated LDL from macrophages. With macrophage activation, plasminogen released about 60% less cholesterol and 63% less TCA-insoluble 125I-aggregated LDL than when macrophages were not activated. Electron microscopy showed that PMA did not cause SCCs to close, which could have trapped aggregated LDL within the SCCs and limited protease access to aggregated LDL. Rather, PMA decreased macrophage generation of plasmin by 61%, and stimulated lysosomal degradation of aggregated LDL by more than 2-fold. Degradation was mediated by protein kinase C, shown by the finding that degradation was inhibited by the protein kinase C inhibitor Gö6976. PMA-stimulated degradation of aggregated LDL was associated with a 3-fold increase in cholesterol esterification, consistent with hydrolysis and re-esterification of aggregated LDL-derived cholesteryl ester.In conclusion, macrophage activation with PMA causes more of the aggregated LDL that enters macrophage SCCs to be metabolized by lysosomes. This results in more cholesterol to be stored in macrophages and less aggregated LDL to be available for plasmin-mediated release from macrophage SCCs.http://www.sciencedirect.com/science/article/pii/S0022227520300596acyl-CoA:cholesterol acyltransferaseatherosclerosischolesterolendocytosisplasminlow density lipoprotein |
| spellingShingle | Wei Huang Itsuko Ishii Wei-Yang Zhang Miyahiko Sonobe Howard S. Kruth PMA activation of macrophages alters macrophage metabolism of aggregated LDL Journal of Lipid Research acyl-CoA:cholesterol acyltransferase atherosclerosis cholesterol endocytosis plasmin low density lipoprotein |
| title | PMA activation of macrophages alters macrophage metabolism of aggregated LDL |
| title_full | PMA activation of macrophages alters macrophage metabolism of aggregated LDL |
| title_fullStr | PMA activation of macrophages alters macrophage metabolism of aggregated LDL |
| title_full_unstemmed | PMA activation of macrophages alters macrophage metabolism of aggregated LDL |
| title_short | PMA activation of macrophages alters macrophage metabolism of aggregated LDL |
| title_sort | pma activation of macrophages alters macrophage metabolism of aggregated ldl |
| topic | acyl-CoA:cholesterol acyltransferase atherosclerosis cholesterol endocytosis plasmin low density lipoprotein |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520300596 |
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