Oxidized calmodulin kinase II regulates conduction following myocardial infarction: A computational analysis

Matthew D. Christensen, Wen Dun, Penelope A. Boyden, Mark Anderson, Peter J. Mohler, Thomas J. Hund

Research output: Contribution to journalArticle

Abstract

Calmodulin kinase II (CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including calcium cycling, hypertrophy and apoptosis. Dysfunction in the CaMKII signaling pathway occurs in heart disease and is associated with increased susceptibility to life-threatening arrhythmia. Furthermore, CaMKII inhibition prevents cardiac arrhythmia and improves heart function following myocardial infarction. Recently, a novel mechanism for oxidative CaMKII activation was discovered in the heart. Here, we provide the first report of CaMKII oxidation state in a well-validated, large-animal model of heart disease. Specifically, we observe increased levels of oxidized CaMKII in the infarct border zone (BZ). These unexpected new data identify an alternative activation pathway for CaMKII in common cardiovascular disease. To study the role of oxidation-dependent CaMKII activation in creating a pro-arrhythmia substrate following myocardial infarction, we developed a new mathematical model of CaMKII activity including both oxidative and autophosphorylation activation pathways. Computer simulations using a multicellular mathematical model of the cardiac fiber demonstrate that enhanced CaMKII activity in the infarct BZ, due primarily to increased oxidation, is associated with reduced conduction velocity, increased effective refractory period, and increased susceptibility to formation of conduction block at the BZ margin, a prerequisite for reentry. Furthermore, our model predicts that CaMKII inhibition improves conduction and reduces refractoriness in the BZ, thereby reducing vulnerability to conduction block and reentry. These results identify a novel oxidation-dependent pathway for CaMKII activation in the infarct BZ that may be an effective therapeutic target for improving conduction and reducing heterogeneity in the infarcted heart.

Original languageEnglish (US)
Article numbere1000583
JournalPLoS Computational Biology
Volume5
Issue number12
DOIs
StatePublished - Dec 2009
Externally publishedYes

Fingerprint

Calmodulin
Calcium-Calmodulin-Dependent Protein Kinases
Myocardial Infarction
Computational Analysis
myocardial infarction
calmodulin
Conduction
phosphotransferases (kinases)
cardiovascular disease
oxidation
Activation
Oxidation
infarction
Chemical activation
arrhythmia
heart
apoptosis
Cardiac Arrhythmias
Pathway
Reentry

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Ecology
  • Molecular Biology
  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Computational Theory and Mathematics

Cite this

Oxidized calmodulin kinase II regulates conduction following myocardial infarction : A computational analysis. / Christensen, Matthew D.; Dun, Wen; Boyden, Penelope A.; Anderson, Mark; Mohler, Peter J.; Hund, Thomas J.

In: PLoS Computational Biology, Vol. 5, No. 12, e1000583, 12.2009.

Research output: Contribution to journalArticle

Christensen, Matthew D. ; Dun, Wen ; Boyden, Penelope A. ; Anderson, Mark ; Mohler, Peter J. ; Hund, Thomas J. / Oxidized calmodulin kinase II regulates conduction following myocardial infarction : A computational analysis. In: PLoS Computational Biology. 2009 ; Vol. 5, No. 12.
@article{eb9627fd73ef46eca7d45ea0748ded2c,
title = "Oxidized calmodulin kinase II regulates conduction following myocardial infarction: A computational analysis",
abstract = "Calmodulin kinase II (CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including calcium cycling, hypertrophy and apoptosis. Dysfunction in the CaMKII signaling pathway occurs in heart disease and is associated with increased susceptibility to life-threatening arrhythmia. Furthermore, CaMKII inhibition prevents cardiac arrhythmia and improves heart function following myocardial infarction. Recently, a novel mechanism for oxidative CaMKII activation was discovered in the heart. Here, we provide the first report of CaMKII oxidation state in a well-validated, large-animal model of heart disease. Specifically, we observe increased levels of oxidized CaMKII in the infarct border zone (BZ). These unexpected new data identify an alternative activation pathway for CaMKII in common cardiovascular disease. To study the role of oxidation-dependent CaMKII activation in creating a pro-arrhythmia substrate following myocardial infarction, we developed a new mathematical model of CaMKII activity including both oxidative and autophosphorylation activation pathways. Computer simulations using a multicellular mathematical model of the cardiac fiber demonstrate that enhanced CaMKII activity in the infarct BZ, due primarily to increased oxidation, is associated with reduced conduction velocity, increased effective refractory period, and increased susceptibility to formation of conduction block at the BZ margin, a prerequisite for reentry. Furthermore, our model predicts that CaMKII inhibition improves conduction and reduces refractoriness in the BZ, thereby reducing vulnerability to conduction block and reentry. These results identify a novel oxidation-dependent pathway for CaMKII activation in the infarct BZ that may be an effective therapeutic target for improving conduction and reducing heterogeneity in the infarcted heart.",
author = "Christensen, {Matthew D.} and Wen Dun and Boyden, {Penelope A.} and Mark Anderson and Mohler, {Peter J.} and Hund, {Thomas J.}",
year = "2009",
month = "12",
doi = "10.1371/journal.pcbi.1000583",
language = "English (US)",
volume = "5",
journal = "PLoS Computational Biology",
issn = "1553-734X",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Oxidized calmodulin kinase II regulates conduction following myocardial infarction

T2 - A computational analysis

AU - Christensen, Matthew D.

AU - Dun, Wen

AU - Boyden, Penelope A.

AU - Anderson, Mark

AU - Mohler, Peter J.

AU - Hund, Thomas J.

PY - 2009/12

Y1 - 2009/12

N2 - Calmodulin kinase II (CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including calcium cycling, hypertrophy and apoptosis. Dysfunction in the CaMKII signaling pathway occurs in heart disease and is associated with increased susceptibility to life-threatening arrhythmia. Furthermore, CaMKII inhibition prevents cardiac arrhythmia and improves heart function following myocardial infarction. Recently, a novel mechanism for oxidative CaMKII activation was discovered in the heart. Here, we provide the first report of CaMKII oxidation state in a well-validated, large-animal model of heart disease. Specifically, we observe increased levels of oxidized CaMKII in the infarct border zone (BZ). These unexpected new data identify an alternative activation pathway for CaMKII in common cardiovascular disease. To study the role of oxidation-dependent CaMKII activation in creating a pro-arrhythmia substrate following myocardial infarction, we developed a new mathematical model of CaMKII activity including both oxidative and autophosphorylation activation pathways. Computer simulations using a multicellular mathematical model of the cardiac fiber demonstrate that enhanced CaMKII activity in the infarct BZ, due primarily to increased oxidation, is associated with reduced conduction velocity, increased effective refractory period, and increased susceptibility to formation of conduction block at the BZ margin, a prerequisite for reentry. Furthermore, our model predicts that CaMKII inhibition improves conduction and reduces refractoriness in the BZ, thereby reducing vulnerability to conduction block and reentry. These results identify a novel oxidation-dependent pathway for CaMKII activation in the infarct BZ that may be an effective therapeutic target for improving conduction and reducing heterogeneity in the infarcted heart.

AB - Calmodulin kinase II (CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including calcium cycling, hypertrophy and apoptosis. Dysfunction in the CaMKII signaling pathway occurs in heart disease and is associated with increased susceptibility to life-threatening arrhythmia. Furthermore, CaMKII inhibition prevents cardiac arrhythmia and improves heart function following myocardial infarction. Recently, a novel mechanism for oxidative CaMKII activation was discovered in the heart. Here, we provide the first report of CaMKII oxidation state in a well-validated, large-animal model of heart disease. Specifically, we observe increased levels of oxidized CaMKII in the infarct border zone (BZ). These unexpected new data identify an alternative activation pathway for CaMKII in common cardiovascular disease. To study the role of oxidation-dependent CaMKII activation in creating a pro-arrhythmia substrate following myocardial infarction, we developed a new mathematical model of CaMKII activity including both oxidative and autophosphorylation activation pathways. Computer simulations using a multicellular mathematical model of the cardiac fiber demonstrate that enhanced CaMKII activity in the infarct BZ, due primarily to increased oxidation, is associated with reduced conduction velocity, increased effective refractory period, and increased susceptibility to formation of conduction block at the BZ margin, a prerequisite for reentry. Furthermore, our model predicts that CaMKII inhibition improves conduction and reduces refractoriness in the BZ, thereby reducing vulnerability to conduction block and reentry. These results identify a novel oxidation-dependent pathway for CaMKII activation in the infarct BZ that may be an effective therapeutic target for improving conduction and reducing heterogeneity in the infarcted heart.

UR - http://www.scopus.com/inward/record.url?scp=74549157674&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=74549157674&partnerID=8YFLogxK

U2 - 10.1371/journal.pcbi.1000583

DO - 10.1371/journal.pcbi.1000583

M3 - Article

C2 - 19997488

AN - SCOPUS:74549157674

VL - 5

JO - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-734X

IS - 12

M1 - e1000583

ER -