Effects of Advanced Glycation End Products on Calcium Handling in Cardiomyocytes

Abstract

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 (ΔF/F0) of 20 m<smlcap>M</smlcap> 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.