Role of activated CaMKII in abnormal calcium homeostasis and INa remodeling after myocardial infarction: Insights from mathematical modeling

Thomas J. Hund, Keith F. Decker, Evelyn Kanter, Peter J. Mohler, Penelope A. Boyden, Richard B. Schuessler, Kathryn A. Yamada, Yoram Rudy

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Ca2+/calmodulin-dependent protein kinase II is a multifunctional serine/threonine kinase with diverse cardiac roles including regulation of excitation contraction, transcription, and apoptosis. Dynamic regulation of CaMKII activity occurs in cardiac disease and is linked to specific disease phenotypes through its effects on ion channels, transporters, transcription and cell death pathways. Recent mathematical models of the cardiomyocyte have incorporated limited elements of CaMKII signaling to advance our understanding of how CaMKII regulates cardiac contractility and excitability. Given the importance of CaMKII in cardiac disease, it is imperative that computer models evolve to capture the dynamic range of CaMKII activity. In this study, using mathematical modeling combined with biochemical and imaging techniques, we test the hypothesis that CaMKII signaling in the canine infarct border zone (BZ) contributes to impaired calcium homeostasis and electrical remodeling. We report that the level of CaMKII autophosphorylation is significantly increased in the BZ region. Computer simulations using an updated mathematical model of CaMKII signaling reproduce abnormal Ca2+ transients and action potentials characteristic of the BZ. Our simulations show that CaMKII hyperactivity contributes to abnormal Ca2+ homeostasis and reduced action potential upstroke velocity due to effects on INa gating kinetics. In conclusion, we present a new mathematical tool for studying effects of CaMKII signaling on cardiac excitability and contractility over a dynamic range of kinase activities. Our experimental and theoretical findings establish abnormal CaMKII signaling as an important component of remodeling in the canine BZ.

Original languageEnglish
Pages (from-to)420-428
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume45
Issue number3
DOIs
StatePublished - Sep 2008

Keywords

  • Arrhythmia
  • Calcium handling
  • Calcium/calmodulin-dependent protein kinase II
  • Mathematical modeling
  • Myocardial infarction

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