High-affinity-receptor-mediated uptake and degradation of glucose-modified proteins: A potential mechanism for the removal of senescent macromolecules

H. Vlassara, M. Brownlee, A. Cerami

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Abstract

Proteins that have been modified by long-term exposure to glucose accumulate advanced glycosylation end products (AGE) as a function of protein age. In these studies, we have characterized the interaction of AGE-protein with mouse peritoneal macrophages, using AGE-modified bovine serum albumin (AGE-BSA, prepared by incubation with glucose) as a probe. AGE-BSA was specifically bound to cells at 4°C and was taken up and degraded at 37°C; these processes were concentration dependent and saturable. Competition experiments with AGE-BSA, BSA incubated with phosphate-buffered saline rather than glucose, and yeast mannan demonstrated that macrophages specifically recognize AGE on proteins by a receptor that is completely distinct from the mannose/fucose receptor. Scatchard analysis of AGE-BSA binding data indicated that there are ~ 1.06 x 105 receptors per macrophage, with an affinity constant of 1.75 x 10-11 M. Specific binding of AGE-BSA to the macrophage receptor was competitively inhibited by BSA that had been chemically coupled to a synthetic analogue of the specific AGE, 2-(2-furoyl)-4(5)-2(furanyl)-1H-imidazole (FFI-BSA). FFI-BSA was also taken up by macrophages in a concentration-dependent, saturable manner. Prior incubation of macrophages with AGE-BSA failed to influence the subsequent uptake and degradation of added AGE-BSA. Thus, the AGE receptor does not appear to be down-regulated by exposure to AGE-proteins. Results from these studies suggest that AGE could act in vivo as a specific signal for recognition and degradation of senescent macromolecules. Incomplete removal of AGE-proteins by macrophages may ultimately give rise to some of the physiologic changes that occur with normal aging.

Original languageEnglish (US)
Pages (from-to)5588-5592
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume82
Issue number17
StatePublished - 1985
Externally publishedYes

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Advanced Glycosylation End Products
Staphylococcal Protein A
Glucose
Macrophages
Proteins
Mannans
Peritoneal Macrophages

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

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title = "High-affinity-receptor-mediated uptake and degradation of glucose-modified proteins: A potential mechanism for the removal of senescent macromolecules",
abstract = "Proteins that have been modified by long-term exposure to glucose accumulate advanced glycosylation end products (AGE) as a function of protein age. In these studies, we have characterized the interaction of AGE-protein with mouse peritoneal macrophages, using AGE-modified bovine serum albumin (AGE-BSA, prepared by incubation with glucose) as a probe. AGE-BSA was specifically bound to cells at 4°C and was taken up and degraded at 37°C; these processes were concentration dependent and saturable. Competition experiments with AGE-BSA, BSA incubated with phosphate-buffered saline rather than glucose, and yeast mannan demonstrated that macrophages specifically recognize AGE on proteins by a receptor that is completely distinct from the mannose/fucose receptor. Scatchard analysis of AGE-BSA binding data indicated that there are ~ 1.06 x 105 receptors per macrophage, with an affinity constant of 1.75 x 10-11 M. Specific binding of AGE-BSA to the macrophage receptor was competitively inhibited by BSA that had been chemically coupled to a synthetic analogue of the specific AGE, 2-(2-furoyl)-4(5)-2(furanyl)-1H-imidazole (FFI-BSA). FFI-BSA was also taken up by macrophages in a concentration-dependent, saturable manner. Prior incubation of macrophages with AGE-BSA failed to influence the subsequent uptake and degradation of added AGE-BSA. Thus, the AGE receptor does not appear to be down-regulated by exposure to AGE-proteins. Results from these studies suggest that AGE could act in vivo as a specific signal for recognition and degradation of senescent macromolecules. Incomplete removal of AGE-proteins by macrophages may ultimately give rise to some of the physiologic changes that occur with normal aging.",
author = "H. Vlassara and M. Brownlee and A. Cerami",
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T1 - High-affinity-receptor-mediated uptake and degradation of glucose-modified proteins

T2 - A potential mechanism for the removal of senescent macromolecules

AU - Vlassara, H.

AU - Brownlee, M.

AU - Cerami, A.

PY - 1985

Y1 - 1985

N2 - Proteins that have been modified by long-term exposure to glucose accumulate advanced glycosylation end products (AGE) as a function of protein age. In these studies, we have characterized the interaction of AGE-protein with mouse peritoneal macrophages, using AGE-modified bovine serum albumin (AGE-BSA, prepared by incubation with glucose) as a probe. AGE-BSA was specifically bound to cells at 4°C and was taken up and degraded at 37°C; these processes were concentration dependent and saturable. Competition experiments with AGE-BSA, BSA incubated with phosphate-buffered saline rather than glucose, and yeast mannan demonstrated that macrophages specifically recognize AGE on proteins by a receptor that is completely distinct from the mannose/fucose receptor. Scatchard analysis of AGE-BSA binding data indicated that there are ~ 1.06 x 105 receptors per macrophage, with an affinity constant of 1.75 x 10-11 M. Specific binding of AGE-BSA to the macrophage receptor was competitively inhibited by BSA that had been chemically coupled to a synthetic analogue of the specific AGE, 2-(2-furoyl)-4(5)-2(furanyl)-1H-imidazole (FFI-BSA). FFI-BSA was also taken up by macrophages in a concentration-dependent, saturable manner. Prior incubation of macrophages with AGE-BSA failed to influence the subsequent uptake and degradation of added AGE-BSA. Thus, the AGE receptor does not appear to be down-regulated by exposure to AGE-proteins. Results from these studies suggest that AGE could act in vivo as a specific signal for recognition and degradation of senescent macromolecules. Incomplete removal of AGE-proteins by macrophages may ultimately give rise to some of the physiologic changes that occur with normal aging.

AB - Proteins that have been modified by long-term exposure to glucose accumulate advanced glycosylation end products (AGE) as a function of protein age. In these studies, we have characterized the interaction of AGE-protein with mouse peritoneal macrophages, using AGE-modified bovine serum albumin (AGE-BSA, prepared by incubation with glucose) as a probe. AGE-BSA was specifically bound to cells at 4°C and was taken up and degraded at 37°C; these processes were concentration dependent and saturable. Competition experiments with AGE-BSA, BSA incubated with phosphate-buffered saline rather than glucose, and yeast mannan demonstrated that macrophages specifically recognize AGE on proteins by a receptor that is completely distinct from the mannose/fucose receptor. Scatchard analysis of AGE-BSA binding data indicated that there are ~ 1.06 x 105 receptors per macrophage, with an affinity constant of 1.75 x 10-11 M. Specific binding of AGE-BSA to the macrophage receptor was competitively inhibited by BSA that had been chemically coupled to a synthetic analogue of the specific AGE, 2-(2-furoyl)-4(5)-2(furanyl)-1H-imidazole (FFI-BSA). FFI-BSA was also taken up by macrophages in a concentration-dependent, saturable manner. Prior incubation of macrophages with AGE-BSA failed to influence the subsequent uptake and degradation of added AGE-BSA. Thus, the AGE receptor does not appear to be down-regulated by exposure to AGE-proteins. Results from these studies suggest that AGE could act in vivo as a specific signal for recognition and degradation of senescent macromolecules. Incomplete removal of AGE-proteins by macrophages may ultimately give rise to some of the physiologic changes that occur with normal aging.

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