The ligand activity of AGE-proteins to scavenger receptors is dependent on their rate of modification by AGEs

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Abstract

The cellular interaction of proteins modified with advanced glycation end-products (AGEs) is believed to induce several different biological responses, which are involved in the development of diabetic vascular complications. We report here that the ratio of protein glycation is implicated in its ligand activity to scavenger receptors. Although highly-modified AGE-bovine serum albumin (high-AGE-BSA) was significantly recognized by human monocyte-derived macrophages and Chinese hamster ovary cells which overexpress such scavenger receptors as CD36, SR-BI (scavenger receptor class B type-I), and LOX-1 (Lectin-like Ox-LDL receptor-1), the mildly-modified-AGE-BSA (mild-AGE-BSA) did not show any ligand activity to these cells. Furthermore, when 111In-labeled high- or mild-AGE-BSA were injected into the tail vein of mice, the high-AGE-BSA was rapidly cleared from the circulation whereas the clearance rate of the mild-AGE-BSA was very slow, similar to the native BSA. These results demonstrate the first evidence that the ligand activity of the AGE-proteins to the scavenger receptors and its pharmacokinetic properties depend on their rate of modification by AGEs, and we should carefully prepare the AGE-proteins in vitro to clarify the physiological significance of the interaction between the AGE-receptors and AGE-proteins.

Abbreviations

AGE(s)
advanced glycation end products
BSA
Bovine serum albumin
High-AGE-BSA
highly modified AGE-BSA
Mild-AGE-BSA
Mildly modified AGE-BSA
GA-AGE-BSA
Glycolaldehyde-derived AGE-BSA
MALDI-TOFMS
Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry
CML
Nε-(carboxymethyl)lysine
ELISA
enzyme-linked immunosorbent assay
PBS
phosphate-buffered saline

Keywords

Advanced glycation end products (AGEs)
Nε-(carboxymethyl)lysine (CML)
Scavenger receptor
Macrophage
Atherosclerosis
Diabetes

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