Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties

C. Esposito, H. Gerlach, J. Brett, David Stern, H. Vlassara

Research output: Contribution to journalArticle

326 Citations (Scopus)

Abstract

Advanced glycosylation end products (AGE) of proteins accumulate in the vasculature with diabetes and aging, and are thought to be associated with vascular complications. This led us to examine the interaction of AGE-BSA as a prototype of this class of nonenzymatically glycosylated proteins subjected to further processing, with endothelium. Incubation of 125I-AGE-BSA with cultured bovine endothelium resulted in time-dependent, saturable binding that was half-maximal at a concentration of ~100 nM. Although unlabeled normal BSA was not a competitor, unlabeled AGE-BSA was an effective competitor of 125I-AGE-BSA-endothelial cell interaction. In addition, AGE modification of two alternative proteins, hemoglobin and ribonuclease, rendered them inhibitors of 125I-AGE-BSA binding to endothelium, although the native, unmodified forms of these proteins were not. At 37°C, binding of 125I-AGE-BSA or gold-labeled AGE-BSA was followed by internalization and subsequent segregation either to a lysosomal compartment or to the endothelial-derived matrix after transcytosis. Exposure of endothelium to AGE-BSA led to perturbation of two important endothelial cell homeostatic properties, coagulant and barrier function. AGE-BSA downregulated the anticoagulant endothelial cofactor thrombomodulin, and induced synthesis and cell surface expression of the procoagulant cofactor tissue factor over the same range of concentrations that resulted in occupancy of cell surface AGE-BSA binding sites. In addition, AGE-BSA increased endothelial permeability, resulting in accelerated passage of an inert macromolecular tracer, [3H]inulin, across the monolayer. These results indicate that AGE derivatives of proteins, potentially important constituents of pathologic vascular tissue, bind to specific sites on the endothelial cell surface and modulate central endothelial cell functions. The interaction of AGE-modified proteins with endothelium may play an important role in the early stages of increased vascular permeability, as well as vessel wall-related abnormalities of the coagulation system, characteristic of diabetes and aging.

Original languageEnglish (US)
Pages (from-to)1387-1407
Number of pages21
JournalJournal of Experimental Medicine
Volume170
Issue number4
DOIs
StatePublished - Jan 1 1989
Externally publishedYes

Fingerprint

Coagulants
Advanced Glycosylation End Products
Surface Properties
Albumins
Permeability
Glucose
Endothelium
Endothelial Cells
Proteins
Blood Vessels
Transcytosis
Thrombomodulin
Inulin
Capillary Permeability
Thromboplastin
Ribonucleases
Cell Communication
Gold

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties. / Esposito, C.; Gerlach, H.; Brett, J.; Stern, David; Vlassara, H.

In: Journal of Experimental Medicine, Vol. 170, No. 4, 01.01.1989, p. 1387-1407.

Research output: Contribution to journalArticle

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