title: Effects of advanced glycation end products on calcium handling in cardiomyocytes.
abstract: OBJECTIVE
  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 Ca(2+) handling in cardiomyocytes to elucidate the possible mechanism underlying cardiac dysfunction in diabetic cardiomypathy.
  
  
  RESULTS
  Confocal imaging Ca(2+) spark, the elementary Ca(2+) release event reflecting RyR activity in intact cell, as well as SR Ca(2+) content and systolic Ca(2+) transient were performed in cultured neonatal rat ventricular myocytes. The results show that 50 mg/ml AGE increased the frequency of Ca(2+) sparks by 160%, while 150 mg/ml AGE increased it by 53%. AGE decreased the amplitude, width and duration of Ca(2+) sparks. Blocking RAGE with anti-RAGE IgG completely abolished the alteration of Ca(2+) sparks. The SR Ca(2+) content indicated by the amplitude (ΔF/F0) of 20 mM caffeine-elicited Ca(2+) transient was significantly decreased by 150 mg/ml AGE. In parallel, the amplitude of systolic Ca(2+) 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 Ca(2+) transient.
  
  
  CONCLUSIONS
  AGE/RAGE signal enhanced Ca(2+) spark-mediated SR Ca(2+) leak, causing partial depletion of SR Ca(2+) content and consequently decreasing systolic Ca(2+) transient, which may contribute to contractile dysfunction in diabetic cardiomyopathy.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Dewen
authors.initials: D
authors.lastname: Yan
authors.forename: Xinping
authors.initials: X
authors.lastname: Luo
authors.forename: Yali
authors.initials: Y
authors.lastname: Li
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Liu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Deng
authors.forename: Na
authors.initials: N
authors.lastname: Zheng
authors.forename: Kaiping
authors.initials: K
authors.lastname: Gao
authors.forename: Qiaobing
authors.initials: Q
authors.lastname: Huang
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D058065:Diabetic Cardiomyopathies / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000494:pharmacology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000276:immunology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*; D013599:Systole / Q000502:physiology
chemical_list: D000906:Antibodies; D002121:Calcium Channel Blockers; D016166:Free Radical Scavengers; D017127:Glycation End Products, Advanced; D007074:Immunoglobulin G; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019837:Ryanodine Receptor Calcium Release Channel; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D002118:Calcium