Cardiac systems biology and parameter sensitivity analysis: intracellular Ca2+ regulatory mechanisms in mouse ventricular myocytes.
Intracellular Ca(2+) dynamics of cardiac myocytes are regulated by complex mechanisms of a variety of ion channels, transporters, and exchangers. Alterations of these Ca(2+) regulatory components might lead to development of cardiac diseases. To investigate the regulatory mechanisms and hidden Ca(2+) dynamics we use integrative systems analysis. Herein, we briefly summarize cardiac systems biology and, within the context of cardiac systems biology, identify the functional role of key Ca(2+) regulatory proteins and their influence on intracellular Ca(2+) dynamics (i.e., Ca(2+) transient, SR Ca(2+) content, CICR gain, half-decay time) using parameter sensitivity analysis based on an experimentally validated mathematical model of mouse ventricular myocytes. In addition, we analyze the influence of the pacing period (frequency) of a stimulus current since most of the Ca(2+) regulatory proteins react with different timescales. Throughout the parameter sensitivity analysis, we found that alteration of SERCA or LTCC has a more significant effect on the Ca(2+) dynamics than that of RyR or NCX. In particular, for the 70% down-regulation of LTCC, the Ca(2+) influx through LTCC failed to initialize the SR Ca(2+) release and thereby the intracellular Ca(2+) dynamics was dramatically changed. We also found that the pacing period has a significant effect on the half-decay time of the Ca(2+) transients. These findings provide us with new insights into the pathophysiology of cardiac failure as well as the development of new therapeutic strategies.
Shin
Sung-Young
SY
Department of Bio and Brain Engineering and KI for the BioCentury, Korea Advanced Institute of Science and Technology, 305-701, Daejeon, Korea.
Choo
Sang-Mok
SM
Woo
Sun-Hee
SH
Cho
Kwang-Hyun
KH
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D003198:Computer Simulation; D051379:Mice; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D049490:Systems Biology / Q000379:methods; D016276:Ventricular Function
D002118:Calcium