Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

Abstract

Accelerated atherosclerosis and microvascular complications are perhaps the leading cause of coronary heart disease, blindness and renal failure which are common complications in patients with prolonged diabetes [1±3]. Plasminogen activator inhibitor-1 (PAI-1) is an important fast-acting serine protease inhibitor that attenuates fibrinolysis [4]. Epidemiological studies have demonstrated that reduced fibrinolytic activity because of elevated plasma PAI-1 is an important factor in various thrombotic diseases such as deep vein thrombosis, ischaemic heart disease [5±8] and diabetic vascular complications [9±10]. In addition to the attenuated fibrinolytic activity, hypercoagulability and platelet hyperaggregation are also prevalent in diabetic patients, contributing to microthrombus formation in diabetic micro-and macroangiopathies [11]. The molecular mechanisms underlying these thrombogenic abnormalities, however, are not fully understood. Diabetologia (1998) Summary Several thrombogenic abnormalities are associated with diabetes. To investigate the underlying molecular mechanisms, we examined the effects of advanced glycation endproducts (AGE), non-enzymatically glycated protein derivatives, on the production of prostacyclin (PGI 2 ), an anti-thrombogenic prostanoid, and of plasminogen activator inhibitor-1 (PAI-1), a fast-acting serine protease inhibitor of fibrinolysis, in human microvascular endothelial cells (EC). Firstly, AGE-bovine serum albumin (BSA) but not non-glycated BSA, was found to considerably decrease the production of PGI 2 to about two-thirds of the control value. Secondly, quantitative reverse transcription-polymerase chain reaction showed that AGE-BSA increased the EC levels of mRNA coding for PAI-1, this being associated with a concomitant increase in the immunoreactive PAI-1 contents and the anti-fibrinolytic activity. Thirdly, the effects of AGE on PGI 2 and PAI-1 syntheses in EC were found to be mediated by a receptor for AGE (RAGE) because antisense DNA against RAGE mRNA could reverse the AGE effects. Further, it was found that AGE decreased the intracellular cyclic AMP concentrations in EC and that cyclic AMP agonists such as dibutyryl cyclic AMP, forskolin and PGI 2 analogue reduced the AGE-stimulated PAI-1 production, suggesting the involvement of cyclic AMP in the AGE-signalling pathway. The results thus suggest that AGE have the ability to cause platelet aggregation and fibrin stabilization, resulting in a predisposition to thrombogenesis and thereby contributing to the development and progression of diabetic vascular complications.[ Diabetologia (1998

Only limited effects of aminoguanidine treatment on peripheral nerve function, (Na + ,K + )-ATPase activity and thrombomodulin expression in streptozotocin-induced diabetic rats

“…In vitro experiments on neuroblastoma cells have shown recently [23] that stimulation of cAMP with subsequent activation of protein kinase A promotes NO production, which in turn enhances (Na + ,K + )-ATPase activity. Because AGE decreases tissue NO and cAMP concentrations [24,25], inhibition of AGE formation by treatment with aminoguanidine may preserve (Na + ,K + )-ATPase activity directly in neuronal tissues or indirectly by correction of nerve blood flow. This notion is supported by recent studies that show that treatment with aminoguanidine together with NO-inhibitor diminished the ameliorative effects of aminoguanidine to improve MNCV delay in diabetic rats [26].…”

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

“…In a study when AGE-modified albumin was administered to nondiabetic rats for 4 weeks, it caused glomerular hypertrophy and increased extracellular matrix production in association with activation of the genes for collagen, laminin, and TGFb [46]. Other observations in diabetic animals are compatible with a pathogenetic role for AGEs in microvascular disease.…”

Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis

“…[28][29][30][31] In addition, the AGE-RAGE axis evokes oxidative stress generation in various cell types via NADPH oxidase activity, which is blocked by cAMP-elevating agents. 3,32,33 Aortic AGEs and oxidative stress levels have been shown to decrease in diabetic RAGE and apolipoprotein E double knockout Figure 1 AGE-modified protein levels (a and b) and RAGE gene expression (c) in the kidneys of Control, DPP-4-deficient, STZ or DPP-4-deficient STZ rats at 9 weeks old. (a) Accumulation levels of AGE-modified protein levels in the kidneys were evaluated by dot blot technique using Bio-Dot SF Microfiltration Apparatus according to the supplier's recommendations.…”