TY - JOUR

T1 - Deleterious effects of reactive aldehydes and glycated proteins on macrophage proteasomal function

T2 - possible links between diabetes and atherosclerosis

AU - Moheimani, Fatemeh

AU - Morgan, Philip E

AU - van Reyk, David M

AU - Davies, Michael Jonathan

N1 - Copyright 2010 Elsevier B.V. All rights reserved.

PY - 2010/6

Y1 - 2010/6

N2 - People with diabetes experience chronic hyperglycemia and are at a high risk of developing atherosclerosis and microvascular disease. Reactions of glucose, or aldehydes derived from glucose (e.g. methylglyoxal, glyoxal, or glycolaldehyde), with proteins result in glycation that ultimately yield advanced glycation end products (AGE). AGE are present at elevated levels in plasma and atherosclerotic lesions from people with diabetes, and previous in vitro studies have postulated that the presence of these materials is deleterious to cell function. This accumulation of AGE and glycated proteins within cells may arise from either increased formation and/or ineffective removal by cellular proteolytic systems, such as the proteasomes, the major multi-enzyme complex that removes proteins within cells. In this study it is shown that whilst high glucose concentrations fail to modify proteasome enzyme activities in J774A.1 macrophage-like cell extracts, reactive aldehydes enhanced proteasomal enzyme activities. In contrast BSA, pre-treated with high glucose for 8 weeks, inhibited both the chymotrypsin-like and caspase-like activities. BSA glycated using methylglyoxal or glycolaldehyde, also inhibited proteasomal activity though to differing extents. This suppression of proteasome activity by glycated proteins may result in further intracellular accumulation of glycated proteins with subsequent deleterious effects on cellular function.

AB - People with diabetes experience chronic hyperglycemia and are at a high risk of developing atherosclerosis and microvascular disease. Reactions of glucose, or aldehydes derived from glucose (e.g. methylglyoxal, glyoxal, or glycolaldehyde), with proteins result in glycation that ultimately yield advanced glycation end products (AGE). AGE are present at elevated levels in plasma and atherosclerotic lesions from people with diabetes, and previous in vitro studies have postulated that the presence of these materials is deleterious to cell function. This accumulation of AGE and glycated proteins within cells may arise from either increased formation and/or ineffective removal by cellular proteolytic systems, such as the proteasomes, the major multi-enzyme complex that removes proteins within cells. In this study it is shown that whilst high glucose concentrations fail to modify proteasome enzyme activities in J774A.1 macrophage-like cell extracts, reactive aldehydes enhanced proteasomal enzyme activities. In contrast BSA, pre-treated with high glucose for 8 weeks, inhibited both the chymotrypsin-like and caspase-like activities. BSA glycated using methylglyoxal or glycolaldehyde, also inhibited proteasomal activity though to differing extents. This suppression of proteasome activity by glycated proteins may result in further intracellular accumulation of glycated proteins with subsequent deleterious effects on cellular function.

KW - Aldehydes

KW - Animals

KW - Atherosclerosis

KW - Cattle

KW - Cell Line

KW - Diabetes Mellitus

KW - Glucose

KW - Glycosylation End Products, Advanced

KW - Humans

KW - In Vitro Techniques

KW - Macrophages

KW - Mice

KW - Proteasome Endopeptidase Complex

KW - Serum Albumin

KW - Serum Albumin, Bovine

U2 - 10.1016/j.bbadis.2010.02.007

DO - 10.1016/j.bbadis.2010.02.007

M3 - Journal article

C2 - 20176104

VL - 1802

SP - 561

EP - 571

JO - Biochimica et Biophysica Acta - Reviews on Cancer

JF - Biochimica et Biophysica Acta - Reviews on Cancer

SN - 0304-419X

IS - 6

ER -