Abstract
Intracellular Ca2+ dynamics of cardiac myocytes are regulated by complex mechanisms of a variety of ion channels, transporters, and exchangers. Alterations of these Ca2+ regulatory components might lead to development of cardiac diseases. To investigate the regulatory mechanisms and hidden Ca2+ 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 Ca2+ regulatory proteins and their influence on intracellular Ca2+ dynamics (i.e., Ca2+ transient, SR Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ release and thereby the intracellular Ca2+ dynamics was dramatically changed. We also found that the pacing period has a significant effect on the half-decay time of the Ca2+ transients. These findings provide us with new insights into the pathophysiology of cardiac failure as well as the development of new therapeutic strategies.
| Original language | English |
|---|---|
| Title of host publication | Protein - Protein Interaction |
| Editors | Meike Werther, Harald Seitz |
| Pages | 25-45 |
| Number of pages | 21 |
| DOIs | |
| Publication status | Published - 10 Sep 2008 |
Publication series
| Name | Advances in Biochemical Engineering/Biotechnology |
|---|---|
| Volume | 110 |
| ISSN (Print) | 0724-6145 |
Keywords
- Ca regulatory mechanism
- Computer simulations
- Functional analysis
- Intracellular Ca dynamics
- Mathematical modeling
- Mouse ventricular myocytes
Cite this
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Cardiac systems biology and parameter sensitivity analysis : Intracellular Ca2+ regulatory mechanisms in mouse ventricular myocytes. / Shin, Sung Young; Choo, Sang Mok; Woo, Sun Hee; Cho, Kwang Hyun.
Protein - Protein Interaction. ed. / Meike Werther; Harald Seitz. 2008. p. 25-45 (Advances in Biochemical Engineering/Biotechnology; Vol. 110).Research output: Chapter in Book/Report/Conference proceeding › Chapter (Book) › Research › peer-review
TY - CHAP
T1 - Cardiac systems biology and parameter sensitivity analysis
T2 - Intracellular Ca2+ regulatory mechanisms in mouse ventricular myocytes
AU - Shin, Sung Young
AU - Choo, Sang Mok
AU - Woo, Sun Hee
AU - Cho, Kwang Hyun
PY - 2008/9/10
Y1 - 2008/9/10
N2 - Intracellular Ca2+ dynamics of cardiac myocytes are regulated by complex mechanisms of a variety of ion channels, transporters, and exchangers. Alterations of these Ca2+ regulatory components might lead to development of cardiac diseases. To investigate the regulatory mechanisms and hidden Ca2+ 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 Ca2+ regulatory proteins and their influence on intracellular Ca2+ dynamics (i.e., Ca2+ transient, SR Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ release and thereby the intracellular Ca2+ dynamics was dramatically changed. We also found that the pacing period has a significant effect on the half-decay time of the Ca2+ transients. These findings provide us with new insights into the pathophysiology of cardiac failure as well as the development of new therapeutic strategies.
AB - Intracellular Ca2+ dynamics of cardiac myocytes are regulated by complex mechanisms of a variety of ion channels, transporters, and exchangers. Alterations of these Ca2+ regulatory components might lead to development of cardiac diseases. To investigate the regulatory mechanisms and hidden Ca2+ 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 Ca2+ regulatory proteins and their influence on intracellular Ca2+ dynamics (i.e., Ca2+ transient, SR Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ release and thereby the intracellular Ca2+ dynamics was dramatically changed. We also found that the pacing period has a significant effect on the half-decay time of the Ca2+ transients. These findings provide us with new insights into the pathophysiology of cardiac failure as well as the development of new therapeutic strategies.
KW - Ca regulatory mechanism
KW - Computer simulations
KW - Functional analysis
KW - Intracellular Ca dynamics
KW - Mathematical modeling
KW - Mouse ventricular myocytes
UR - http://www.scopus.com/inward/record.url?scp=51049084169&partnerID=8YFLogxK
U2 - 10.1007/10_2007_093
DO - 10.1007/10_2007_093
M3 - Chapter (Book)
SN - 9783540688174
T3 - Advances in Biochemical Engineering/Biotechnology
SP - 25
EP - 45
BT - Protein - Protein Interaction
A2 - Werther, Meike
A2 - Seitz, Harald
ER -