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CaMKII Phosphorylation of RyR2 Mediates Heart Failure Development
Author(s) -
Oort Ralph Jeroen,
Respress Jonathan L,
De Almeida Angela C,
Sarma Satyam,
Li Na,
Skapura Darlene G,
Wehrens Xander H
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.791.7
Subject(s) - ryanodine receptor 2 , heart failure , phosphorylation , pressure overload , ryanodine receptor , medicine , endocrinology , cardiac function curve , ejection fraction , chemistry , cardiology , biology , calcium , microbiology and biotechnology , cardiac hypertrophy
Abnormal regulation of cardiac ryanodine receptor RyR2 by Ca 2+ /calmodulin‐dependent protein kinase 2 (CaMKII) has been identified as a potential cause of Ca 2+ leakage and contractile dysfunction in heart failure. To test the hypothesis that CaMKII phosphorylation of RyR2 is crucial for heart failure development, we generated RyR2 knockin mice in which the CaMKII phosphorylation site S2814 is either mutated into aspartate (SD) to mimic CaMKII phosphorylation, or into alanine (SA) to prevent phosphorylation. Echocardiography revealed a decrease in cardiac function in SD mice at 12 months of age. Both WT and SA mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. At 8 weeks after TAC, SA mice displayed a similar hypertrophic response as WT TAC mice. At 16 weeks after TAC, however, ejection fraction was significantly higher in SA mice compared to WT TAC mice, indicating an inhibition of heart failure development. This rescue effect was further verified by a lower lung‐weight‐to‐tibia‐length ratio and a decrease in expression levels of cardiac stress genes in SA mice. Furthermore, Ca 2+ imaging in isolated cardiomyocytes demonstrated a decreased SR Ca 2+ leak in SA TAC mice. Our results demonstrate that CaMKII phosphorylation of RyR2 is both sufficient and necessary for heart failure development. R.J.v.O. is recipient of the APS Postdoctoral Fellowship in Physiological Genomics