Inhibition of CaMKII Phosphorylation of RyR2 Prevents Induction of Atrial Fibrillation in FKBP12.6 Knockout Mice

DOI Web Site 6 Citations
  • Na Li
    From the Department of Molecular Physiology and Biophysics (N.L., T.W., W.W., Q.W., X.H.T.W.) and the Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH (M.J.C., D.S.R.); and the Division of Experimental Cardiology (N.V., D.D.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • Tiannan Wang
    From the Department of Molecular Physiology and Biophysics (N.L., T.W., W.W., Q.W., X.H.T.W.) and the Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH (M.J.C., D.S.R.); and the Division of Experimental Cardiology (N.V., D.D.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • Wei Wang
    From the Department of Molecular Physiology and Biophysics (N.L., T.W., W.W., Q.W., X.H.T.W.) and the Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH (M.J.C., D.S.R.); and the Division of Experimental Cardiology (N.V., D.D.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • Michael J. Cutler
    From the Department of Molecular Physiology and Biophysics (N.L., T.W., W.W., Q.W., X.H.T.W.) and the Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH (M.J.C., D.S.R.); and the Division of Experimental Cardiology (N.V., D.D.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • Qiongling Wang
    From the Department of Molecular Physiology and Biophysics (N.L., T.W., W.W., Q.W., X.H.T.W.) and the Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH (M.J.C., D.S.R.); and the Division of Experimental Cardiology (N.V., D.D.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • Niels Voigt
    From the Department of Molecular Physiology and Biophysics (N.L., T.W., W.W., Q.W., X.H.T.W.) and the Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH (M.J.C., D.S.R.); and the Division of Experimental Cardiology (N.V., D.D.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • David S. Rosenbaum
    From the Department of Molecular Physiology and Biophysics (N.L., T.W., W.W., Q.W., X.H.T.W.) and the Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH (M.J.C., D.S.R.); and the Division of Experimental Cardiology (N.V., D.D.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • Dobromir Dobrev
    From the Department of Molecular Physiology and Biophysics (N.L., T.W., W.W., Q.W., X.H.T.W.) and the Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH (M.J.C., D.S.R.); and the Division of Experimental Cardiology (N.V., D.D.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • Xander H.T. Wehrens
    From the Department of Molecular Physiology and Biophysics (N.L., T.W., W.W., Q.W., X.H.T.W.) and the Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH (M.J.C., D.S.R.); and the Division of Experimental Cardiology (N.V., D.D.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Description

<jats:sec> <jats:title> <jats:underline>Rationale:</jats:underline> </jats:title> <jats:p> Abnormal calcium release from sarcoplasmic reticulum (SR) is considered an important trigger of atrial fibrillation (AF). Whereas increased Ca <jats:sup>2+</jats:sup> /calmodulin-dependent protein kinase II (CaMKII) activity has been proposed to contribute to SR leak and AF induction, downstream targets of CaMKII remain controversial. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <jats:p>To test the hypothesis that inhibition of CaMKII-phosphorylated type-2 ryanodine receptors (RyR2) prevents AF initiation in FKBP12.6-deficient (−/−) mice.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <jats:p> Mice lacking RyR2-stabilizing subunit FKBP12.6 had a higher incidence of spontaneous and pacing-induced AF compared with wild-type mice. Atrial myocytes from FKBP12.6−/− mice exhibited spontaneous Ca <jats:sup>2+</jats:sup> waves (SCaWs) leading to Na <jats:sup>+</jats:sup> /Ca <jats:sup>2+</jats:sup> -exchanger activation and delayed afterdepolarizations (DADs). Mutation S2814A in RyR2, which inhibits CaMKII phosphorylation, reduced Ca <jats:sup>2+</jats:sup> spark frequency, SR Ca <jats:sup>2+</jats:sup> leak, and DADs in atrial myocytes from FKBP12.6−/−:S2814A mice compared with FKBP12.6−/− mice. Moreover, FKBP12.6−/−:S2814A mice exhibited a reduced susceptibility to inducible AF, whereas FKBP12.6−/−:S2808A mice were not protected from AF. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Conclusions:</jats:underline> </jats:title> <jats:p> FKBP12.6 mice exhibit AF caused by SR Ca <jats:sup>2+</jats:sup> leak, Na <jats:sup>+</jats:sup> /Ca <jats:sup>2+</jats:sup> -exchanger activation, and DADs, which promote triggered activity. Genetic inhibition of RyR2-S2814 phosphorylation prevents AF induction in FKBP12.6−/− mice by suppressing SR Ca <jats:sup>2+</jats:sup> leak and DADs. These results suggest suppression of RyR2-S2814 phosphorylation as a potential anti-AF therapeutic target. </jats:p> </jats:sec>

Journal

  • Circulation Research

    Circulation Research 110 (3), 465-470, 2012-02-03

    Ovid Technologies (Wolters Kluwer Health)

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