Effects of Advanced Glycation End Products on Calcium Handling in Cardiomyocytes

Background and Aims: Advanced glycation end products (AGEs) accumulate in diabetes and the engagement of receptor for AGE (RAGE) by AGEs contributes to the pathogenesis of diabetic cardiomyopathy. This study aims to investigate the effects of AGE/RAGE on ryanodine receptor (RyR) activity and Ca2+ handling in cardiomyocytes to elucidate the possible mechanism underlying cardiac dysfunction in diabetic cardiomypathy. Methods and Results: Confocal imaging Ca2+ spark, the elementary Ca2+ release event reflecting RyR activity in intact cell, as well as SR Ca2+ content and systolic Ca2+ transient were performed in cultured neonatal rat ventricular myocytes. The results show that 50 mg/ml AGE increased the frequency of Ca2+ sparks by 160%, while 150 mg/ml AGE increased it by 53%. AGE decreased the amplitude, width and duration of Ca2+ sparks. Blocking RAGE with anti-RAGE IgG completely abolished the alteration of Ca2+ sparks. The SR Ca2+ content indicated by the amplitude (Delta F/F0) of 20 mM caffeine-elicited Ca2+ transient was significantly decreased by 150 mg/ml AGE. In parallel, the amplitude of systolic Ca2+ transient evoked by 1 Hz-field stimulation was remarkably decreased by 150 mg/ml AGE. The anti-RAGE antibody completely restored the impaired SR load and systolic Ca2+ transient. Conclusion: AGE/RAGE signal enhanced Ca2+ spark-mediated SR Ca2+ leak, causing partial depletion of SR Ca2+ content and consequently decreasing systolic Ca2+ transient, which may contribute to contractile dysfunction in diabetic cardiomyopathy. (C) 2014 S. Karger AG, Basel