Delayed intervention with AGE inhibitors attenuates the progression of diabetes-accelerated atherosclerosis in diabetic apolipoprotein E knockout mice

Abstract

Aims/hypothesis Formation of AGEs is increased in the diabetic milieu, which contributes to accelerated atherogenesis. We studied whether delayed treatment with AGE-inhibiting compounds, alagebrium chloride and pyridoxamine dihydrochloride, affected established atherosclerosis in experimental diabetes in comparison with the angiotensin-converting enzyme inhibitor, quinapril. Methods Streptozotocin-induced diabetic male Apoe −/− mice (n=24 per group) received, by oral gavage, from week 10 to 20 of diabetes: no treatment; alagebrium (1 mg kg −1 day −1 ); pyridoxamine (1 g/l in drinking water); or quinapril (30 mg kg −1 day −1 ). Atherosclerotic lesion area (en face analysis) was evaluated for all groups. Results Delayed intervention with alagebrium decreased plaque area in the diabetic Apoe −/− mice compared with untreated mice (total plaque area: alagebrium 10.6±1.6%, untreated, 15.1±1.5%, p<0.05). This anti-atherosclerotic effect was comparable with that achieved with quinapril (quinapril 8.4±1.4%, vs untreated, p<0.05). Pyridoxamine also attenuated plaque development in diabetic mice (5.7± 1.2% vs untreated 11.9 ± 1.1%, p < 0.05). The antiatherosclerotic effect conferred by alagebrium and quinapril was associated with a significant reduction in vascular oxidative stress and circulating AGEs and methylglyoxal, although preformed AGEs were not removed from the vascular wall with either delayed intervention. Conclusions/interpretation Inhibition of AGE accumulation, using a delayed intervention with alagebrium or pyridoxamine, significantly attenuated the progression of established diabetes-associated atherosclerosis, similar to results obtained with quinapril. These findings provide further evidence that blockade of AGE-mediated pathways may present a novel therapy for the prevention of atherosclerosis in diabetes.

Role of bone-marrow- and non-bone-marrow-derived receptor for advanced glycation end-products (RAGE) in a mouse model of diabetes-associated atherosclerosis

“…Collagen is a critical component of atherosclerotic lesions [8,32]. In the present study, increased aortic gene expression of collagens I and III was observed in diabetic global ApoE − / − mice, which is consistent with our previous studies [2,8].…”

“…Extracellular matrix proteins and MMPs are critical components of atherosclerotic lesions [8,32]. The stability of an atherosclerotic plaque depends on the interplay between collagens, which provide plaque stability, and MMPs, which degrade collagen and extracellular matrix, potentially weakening the plaque.…”

Plasma Advanced Glycation End Products Are Associated With Incident Cardiovascular Events in Individuals With Type 2 Diabetes: A Case-Cohort Study With a Median Follow-up of 10 Years (EPIC-NL)

“…Several AGE-lowering compounds have been shown to reduce atherosclerosis in animal models (4,5), demonstrating that AGEs are no innocent bystanders and are of importance for the development of CVD.…”

Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes

“…One key pathway is the increased production of reactive dicarbonyls generated from triose phosphate intermediates of glycolysis, glycerol and ketone peroxidation, overactivation of the polyol pathway, and the degradation of glycated proteins (3)(4)(5)(6). In experimental diabetes, circulating and tissue levels of methylglyoxal (MG) are three to five times higher than in the nondiabetic state (7,8). Plasma MG concentrations are also elevated in patients with diabetes (9), especially those with vascular complications (10).…”

“…Carbonyl-derived AGEs have been detected within atherosclerotic lesions in both extra-and intracellular locations and correlate with the size, complexity, and stability of the lesions (12,13). The potential importance of a-dicarbonyls in the pathogenesis of glucose-dependent atherogenesis is illustrated by the vasculoprotective effects of dicarbonyl scavengers in diabetes, in the absence of euglycemia (7,14).…”