Contents

๐Ÿ“’ Christensen 2009

Oxidized calmodulin kinase II regulates conduction following myocardial infarction: a computational analysis1

Sciwheel.

Introduction

  • Calmodulin kinase II (CaMKII) mediates diverse roles in the heart, including excitation-contraction coupling, sinus node automaticity, apoptosis, hypertrophy, and gene transcription
  • CaMKII overexpression occurs in human heart failure
  • CaMKII is activated by binding of Ca2+/calmodulin, autophosphorylation, oxidation, etc
  • Building a model to investigate a role for oxidized CaMKII in regulating refractoriness and conduction in the infarct BZ

Materials and Methods

Experimental model

  • total coronary artery occlusion for adult mongrel(mix) dogs

In silico model

  • Cellular model: Hund-Rudy dynamic (HRd) dog CMC model with CaMKII
  • PDE solved numerically by the Crank-Nicholson implicit method: $$ -\frac{\partial I_{\alpha x}}{\partial x}=\frac{a}{2 R_{i}} \cdot \frac{\partial^{2} V_{m}(x, t)}{\partial x^{2}}=C_{m} \frac{\partial V_{m}(x, t)}{\partial t}+\sum I_{i o n} $$
  • cycle length โ€Š=โ€Š500 ms, stimulus amplitude โ€Š=โ€Šโˆ’450 ยตA/ยตF, stimulus duration โ€Š=โ€Š0.5 ms

Results

CaMKII is oxidized in the infarct border zone

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1000583.g001

Model of oxidative CaMKII activation and action potential propagation

TextS1

  • include a new model of CaMKII activity based on the simplified scheme proposed by Dupont et al https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1000583.g002

  • includes an oxidized active state in addition to a Ca2+/CaM bound active state and an autophosphorylated active state

  • Ca2+/CaM must bind to a subunit before oxidation may occur

  • Rate constants for state transitions were taken from the literature or chosen to fit experimental data. TableS3

  • the model predicts a secondary increase in the fraction of autophosphorylated CaMKII subunits with an increase in oxidized subunits due to oxidative stress

  • we assume [ROS]โ€Š=โ€Š1.0 ยตM in the BZ, and explore a range of ROS levels from 0 to 10 ยตM

  • oxidation rather than autophosphorylation is the primary determinant of increased CaMKII activity in the BZ model

  • Activated CaMKII altered L-type Ca2+ current, transient outward K+ current, and Na+ current

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1000583.g003

CaMKII regulates INa inactivation in border zone

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1000583.g004

  • CaMKII activation decreased INa availability in BZ
  • differences in INa inactivation between NZ and BZ observed under control conditions are largely eliminated upon CaMKII inhibition

CaMKII regulates conduction in border zone

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1000583.g005

  • enhanced CaMKII activity promote slow conduction in the BZ
  • Making CaMKII resistant to oxidation increased conduction velocity at all diastolic potentials in the BZ with a greater effect at more depolarized diastolic potential
  • In contrast, the BZ model resistant to CaMKII autophosphorylation showed very little improvement in conduction (oxidation predominates)

CaMKII regulates effective refractory period in border zone

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1000583.g006

  • Effective refractory period (ERP) of the action potential is dramatically prolonged in BZ compared to NZ
  • ERP is much greater in the BZ model (213 ms compared to 181 in the NZ)
  • Making CaMKII resistant to oxidative activation reduces ERP to 207 ms in the BZ model despite a slight prolongation of APD
  • These results suggest that oxidation-dependent CaMKII activation contributes to large gradients of refractoriness, particularly at the margins of the infarct BZ, by regulating INa kinetics.

CaMKII increases vulnerability to conduction block

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1000583.g007 https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1000583.g008

  • oxidation-dependent CaMKII activation increases the vulnerability to conduction block at the BZ margin

Discussion

  • first evidence for oxidation of CaMKII as an important component of the remodeling process following MI

Observations

  1. Significant oxidative activation of the kianse occurs under pathophysiological conditions
  2. Oxidative stress may activate the kinase not only through direct oxidation but also through a secondary increase in autophosphorylation
  3. Changes in Na+ channel kinetics due to oxidative CaMKII activation are sufficient to impact conduction in the BZ
  • consistent with experimental studies in mice that over-express CaMKIIฮด

Limitations

  • CaMKII in the model detects a subspace pool of Ca2+ that reaches concentrations somewhere between cytosolic and dyadic concentrations (peak concentration 10โ€“20 ยตM), more semnsitive to oxidation than cytosolic CaMKII

Reference


  1. Christensen MD, Dun W, Boyden PA, Anderson ME, Mohler PJ, Hund TJ. Oxidized calmodulin kinase II regulates conduction following myocardial infarction: a computational analysis. PLoS Comput Biol. 2009;5(12):e1000583. PMC2778128 ↩︎