Advanced Glycation End Product Interventions Reduce Diabetes-Accelerated Atherosclerosis

Abstract

Advanced glycation end product (AGE) formation may contribute to the progression of atherosclerosis, particularly in diabetes. The present study explored atherosclerosis in streptozotocin-induced diabetic apolipoprotein E-deficient (apoE؊/؊) mice that were randomized (n ‫؍‬ 20) to receive for 20 weeks no treatment, the AGE cross-link breaker ALT-711, or the inhibitor of AGE formation aminoguanidine (AG). A sixfold increase in plaque area with diabetes was attenuated by 30% with ALT-711 and by 40% in AG-treated mice. Regional distribution of plaque demonstrated no reduction in plaque area or complexity within the aortic arch with treatment, in contrast to the thoracic and abdominal aortas, where significant attenuation was seen. Diabetes-associated accumulation of AGEs in aortas and plasma and decreases in skin collagen solubility were ameliorated by both treatments, in addition to reductions in the vascular receptor for AGE. Collagenassociated reductions in the AGEs carboxymethyllysine and carboxyethyllysine were identified with both treatments. Diabetes was also accompanied by aortic accumulation of total collagen, specifically collagens I, III, and IV, as well as increases in the profibrotic cytokines transforming growth factor-␤ and connective tissue growth factor and in cellular ␣-smooth muscle actin. Attenuation of these changes was seen in both treated diabetic groups. ALT-711 and AG demonstrated the ability to reduce vascular AGE accumulation in addition to attenuating atherosclerosis in these diabetic mice.

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

“…In particular, nitration and chlorination of apoA-I also occur in diabetes, damaging apoA-I functionality [13,45,46]. While the relative contribution of AGE modification to the overall effect of diabetes on apoA-I dysfunction is yet to be established, it is clear that interventions to reduce AGE levels in diabetes are anti-atherosclerotic [47].…”

A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products

“…Low molecular weight (LMW) AGE fluorescence was assayed as described previously [15]. LMW fluorescence was expressed as arbitrary units, defined by the ratio of the area under the fluorescence curve divided by the area under the A 280 curve, normalised to the values derived following exhaustive enzymatic hydrolysis of AGE albumin [9].…”

“…AGE are thought to have an important role in the pathogenesis of the endorgan damage associated with diabetes. Their importance as mediators of renal injury has been amply demonstrated by studies using inhibitors of AGE formation [13][14][15] or dietary restriction of AGEs [16] to retard nephropathy without influencing glycaemic control. In addition, in vivo exposure of healthy adult animals to AGEs is able to generate glomerular lesions similar to those seen in diabetes, in the absence of hyperglycaemia [7,17].…”

The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

“…Indeed, macrovascular complications account for more than 50% of deaths in people with diabetes. While it is understood that both metabolic and haemodynamic factors such as hyperglycaemia, hyperlipidaemia and dysregulation of the renin-angiotensin system contribute to diabetesassociated atherosclerosis [1][2][3], other less traditional pathways, such as oxidative stress and advanced glycation, are now considered to play an important role in the development of diabetic macrovascular disease [4,5].…”