Contents

📒 Foteinou 2015

Mechanistic investigation of the arrhythmogenic role of oxidized camkii in the heart1

Sciwheel

Introduction

  • ROS overactivates CaMKII => altered excitation-contraction coupling (ECC) and proarrhythmic electrical remodeling
  • Activated CaMKII molecules can be autophosphorylated, retaining activity even upon dissociation of Ca2+/CaM
  • oxidation activation at specific methionine residues of CaMKII, increasing early and delayed afterdepolarizations (EADs and DADs)
  • CaMKII phosphorylates several proteins involved in ECC, including L-type Ca2+ channels (LCCs), ryanodine receptors (RyRs), phospholamban (PLB)
  • also phosphorylates sodium (Na+) and potassium (K+) channels to regulate their function

Materials and Methods

Stochastic model of cardiac CaMKII activation

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  • specifically for CaMKIIδ (cardiac)
  • estricting CaMKII autophoshorylation events to occur only between adjacent CaMKII subunits

Whole-cell model

  • stochastic local-control ventricular myocyte model
  • incorporates the functional effects of CaMKII-mediated phosphorylation of LCCs, RyRs, PLB, and Na+ channels

Results

Rate dependence of H2O2-induced EADs

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Synergy between INaL, ICaL, and INCX on EAD genesis by H2O2

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CaMKII-INaL positive feedback loop in the presence of H2O2

  • CaMKII enhances INaL. increase in INaL is sufficient to activate CaMKII (and enhance target phosphorylation) via elevation of [Ca2+]i mediated by reverse-mode NCX activity

Discussion

  • oxidative activation of both ICaL and INaL lengthens the APD and forms a conditioning phase that facilitates the synergy between INCX and ICaL reactivation
  • ICaL significantly decreased due to shifts of LCC gating toward more inactivation via CDI and/or VDI.

Limitations

  • H2O2 model predicts an increase in SR Ca2+ leak (6-fold), ∼15-fold less than that measured experimentally
  • CaMKII-independent mechanisms of ROS-mediated alteration of cardiac ECC
  • unable to replicate H2O2-induced Na+ and Ca2+ overload and the subsequent occurrence of DADs
  • does not incorporate CaMKII-dependent alterations of the transient outward K+ current (Ito), which tends to increase Ito and shorten APD in rabbit ventricular myocytes

Reference


  1. Foteinou PT, Greenstein JL, Winslow RL. Mechanistic investigation of the arrhythmogenic role of oxidized camkii in the heart. Biophys. J. 2015;109(4):838-849. doi:10.1016/j.bpj.2015.06.064. PMC4547162 ↩︎