Role of activated CaMKII in abnormal calcium homeostasis and I(Na) remodeling after myocardial infarction: insights from mathematical modeling.
Ca(2+)/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 Ca(2+) transients and action potentials characteristic of the BZ. Our simulations show that CaMKII hyperactivity contributes to abnormal Ca(2+) homeostasis and reduced action potential upstroke velocity due to effects on I(Na) 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.
Hund
Thomas J
TJ
Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA. thomas-hund@uiowa.edu
Decker
Keith F
KF
Kanter
Evelyn
E
Mohler
Peter J
PJ
Boyden
Penelope A
PA
Schuessler
Richard B
RB
Yamada
Kathryn A
KA
Rudy
Yoram
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D004285:Dogs; D004789:Enzyme Activation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D007424:Intracellular Fluid / Q000201:enzymology / Q000378:metabolism; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D010496:Pericardium / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*
D012964:Sodium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium