Oxidation- and CaMKII-mediated sarcoplasmic reticulum Ca(2+) leak triggers atrial fibrillation in aging

Xiaoxiao Guo, Su Yuan, Zhenyu Liu, Quan Fang
Journal of Cardiovascular Electrophysiology 2014, 25 (6): 645-52

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.

METHODS AND 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.

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