title: Oxidation- and CaMKII-mediated sarcoplasmic reticulum Ca(2+) leak triggers atrial fibrillation in aging.
abstract: BACKGROUND
  Advanced age is a well-recognized predisposition to atrial fibrillation (AF). However, the cellular electrophysiological changes that underlie the heightened susceptibility to AF in aged individuals remain poorly understood. Sarcoplasmic reticulum (SR) Ca(2+) leak that results from posttranslational modification of type 2 ryanodine receptor channels (RyR2) has been implicated in arrhythmogenesis. We hypothesize that aging alters atrial myocytes Ca(2+) homeostasis and RyR2 function, which create a substrate for AF initiation.
  
  
  RESULTS
  We examined the susceptibility to AF in aged (24 months) and young adult (4-5 months) mice using an intraesophageal atrial electrical stimulation protocol. Aged mice showed significant higher AF induction rate (43.3%, n = 30) than young adults (8.8%, n = 34, P < 0.01). In accordance with these in vivo findings, significantly increased diastolic SR Ca(2+) leak and arrhythmogenic Ca(2+) activities with reduced SR Ca(2+) content were observed in aged atrial myocytes. Western blot showed RyR2 oxidation and phosphorylation at Ser2814 (Ca(2+) /calmodulin-dependent protein kinase II [CaMKII] site), but not phosphorylation at Ser2808 (protein kinase A [PKA] and CaMKII site), were increased in aged atrial myocytes. The selective CaMKII inhibitor (KN-93), as well as the antioxidant reagent (DTT) reversed the diastolic Ca(2+) leak and the frequency of spontaneous Ca(2+) transients in aged atrial myocytes, whereas PKA inhibition with H-89 was ineffective.
  
  
  CONCLUSIONS
  Aging increases both the oxidation and CaMKII-phosphorylation of RyR2, which result in diastolic SR Ca(2+) leak and facilitate AF initiation. These results contribute to the electrophysiological remodeling of aged atria and suggest a therapeutic strategy for AF treatment in aging.
authors.affiliation: Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Guo
authors.forename: Su
authors.initials: S
authors.lastname: Yuan
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Liu
authors.forename: Quan
authors.initials: Q
authors.lastname: Fang
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; C000592748:ryanodine receptor 2. mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Ca2+/calmodulin-dependent protein kinase II; SR Ca2+ leak; aging; atrial fibrillation; oxidation; ryanodine receptor type 2