Abstract 12878: The Effect of Advanced Glycation End Products (AGE) Breaker, Alagebrium on the Cardiac Structural and Functional Change in Type I Diabetic Rat Model
Background: Chronic hyperglycemia contributes to diabetic complications through the formation of advanced glycation end products (AGEs). The crosslink breaker, 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711), alagebrium chloride is known to reduce the pathological condition through breaking AGE cross-links. However, there has been little assessment regarding the impact of alagebrium on AGE-dependent signaling or restoring structural molecular physiology as well as the myocardial functional change.
Methods: We investigated the effect of alagebrium on myocardial functional change using echocardiography as well as structural change in diabetic rat model based on the cellular mechanism.
Results: AGE enhanced reactive oxygen species (ROS) synthesis dose-dependently in cardiomyocytes. Alagebrium induced decrease in enhanced ROS synthesis by AGE and increased expression of receptor for AGE (RAGE). In western blot and RT-PCR experiments, alagebrium also inhibited AGE-induced activation of MAP Kinase and decreased AGE-induced connective tissue growth factor (CTGF) and extracellular matrix. In echocardiography, the left ventricular (LV) dimension was increased (6.33 ±0.58mm at initial vs. 8.33±0.32mm at 16weeks after diabetes, p=0.003), and systolic contractility in radial and circumferential direction was decreased as diabetes was progressed in diabetic rat model. Diabetic progress also modified collagen structure. However, the alagebrium treatment reversed these LV remodeling (8.33±0.32mm at initial vs. 7.03±0.46mm at 4weeks after medication, p=0.049) and systolic dysfunction. The value of radial strain improved from 15.2±5.8% to 38.7±6.9% at 4weeks after medication. (p=0.032)
Conclusion: In conclusion, alagebrium treatment in diabetic rat heart improved myocardial systolic dysfunction and LV remodeling by blocking the AGE-induced intracellular ROS synthesis resulting in inhibition of contractile dysfunction induced by AGE. The beneficial effect of alagebrium on diabetic cardiomyopathy was mediated by reduction of extracellular matrix production and this might be mediated by decreased activation of ERK (extracellular signal-regulated kinase) MAP kinase.
Author Disclosures: H. Seo: None. N. Lee: None. Y. Cho: None. H. Choi: None. J. Suh: None.
- © 2015 by American Heart Association, Inc.