Breakers of advanced glycation end products restore large artery properties in experimental diabetes

Abstract

Glucose and other reducing sugars react with proteins by a nonenzymatic, posttranslational modification process called nonenzymatic glycation. The formation of advanced glycation end products (AGEs) on connective tissue and matrix components accounts largely for the increase in collagen crosslinking that accompanies normal aging and which occurs at an accelerated rate in diabetes, leading to an increase in arterial stiffness. A new class of AGE crosslink "breakers" reacts with and cleaves these covalent, AGE-derived protein crosslinks. Treatment of rats with streptozotocin-induced diabetes with the AGE-breaker ALT-711 for 1-3 weeks reversed the diabetes-induced increase of large artery stiffness as measured by systemic arterial compliance, aortic impedance, and carotid artery compliance and distensibility. These findings will have considerable implications for the treatment of patients with diabetes-related complications and aging.

Figures

Figure 1

ALT-711 significantly increases in vivo carotid artery cross-sectional compliance as assessed by ultrasound in diabetic animals, and animals treated with ALT-711 for 1 or 3 weeks. # reflects P = 0.017 (by ANOVA) for animals treated for 1 week, and P = 0.012 for those treated for 3 weeks.

Figure 2

ALT-711 improves in vitro carotid artery cross-sectional compliance and distensibility with increasing duration of treatment. Compliance and distensibility were calculated based on the increase of diameter and subsequent lumen area when pressure was increased from 75 to 125 mmHg under no flow conditions. #, P < 0.05 by ANOVA compared with diabetic animals.

Figure 3

Chronic treatment with ALT-711 increases pepsin-induced tail tendon collagen solubility in diabetic rats. §, P < 0.05 vs. age-matched nondiabetic control animals; #, P < 0.05 vs. diabetic animals. The ALT-711 group reflect animals that were treated for 3 weeks (1 mg/kg daily by i.p. injection).

Figure 4

ALT-711 decreases IgG crosslinked to the RBC surface. (Upper) Chronic treatment decreases RBC-IgG already after 1 week of chronic dosing. Values are means ± SD of the percent change with respect to day 0. All time points P < 0.01 vs. predose and vs. vehicle. (Lower) RBC-IgG levels decrease dose-dependently after 8 days of oral dosing with ALT-711. Diabetic rats were treated for 8 days with ALT-711 in doses varying from 0.01 to 10 mg/kg. All doses in the range 0.03–10.0 are P < 0.01 vs. predose values.