Cardiac systems biology and parameter sensitivity analysis

Intracellular Ca2+ regulatory mechanisms in mouse ventricular myocytes

Sung Young Shin, Sang Mok Choo, Sun Hee Woo, Kwang Hyun Cho

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Researchpeer-review

8 Citations (Scopus)

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 languageEnglish
Title of host publicationProtein - Protein Interaction
EditorsMeike Werther, Harald Seitz
Pages25-45
Number of pages21
DOIs
Publication statusPublished - 10 Sep 2008

Publication series

NameAdvances in Biochemical Engineering/Biotechnology
Volume110
ISSN (Print)0724-6145

Keywords

  • Ca regulatory mechanism
  • Computer simulations
  • Functional analysis
  • Intracellular Ca dynamics
  • Mathematical modeling
  • Mouse ventricular myocytes

Cite this

Shin, S. Y., Choo, S. M., Woo, S. H., & Cho, K. H. (2008). Cardiac systems biology and parameter sensitivity analysis: Intracellular Ca2+ regulatory mechanisms in mouse ventricular myocytes. In M. Werther, & H. Seitz (Eds.), Protein - Protein Interaction (pp. 25-45). (Advances in Biochemical Engineering/Biotechnology; Vol. 110). https://doi.org/10.1007/10_2007_093
Shin, Sung Young ; Choo, Sang Mok ; Woo, Sun Hee ; Cho, Kwang Hyun. / Cardiac systems biology and parameter sensitivity analysis : Intracellular Ca2+ regulatory mechanisms in mouse ventricular myocytes. Protein - Protein Interaction. editor / Meike Werther ; Harald Seitz. 2008. pp. 25-45 (Advances in Biochemical Engineering/Biotechnology).
@inbook{14981d670f724f8d8590b62382758fd1,
title = "Cardiac systems biology and parameter sensitivity analysis: Intracellular Ca2+ regulatory mechanisms in mouse ventricular myocytes",
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.",
keywords = "Ca regulatory mechanism, Computer simulations, Functional analysis, Intracellular Ca dynamics, Mathematical modeling, Mouse ventricular myocytes",
author = "Shin, {Sung Young} and Choo, {Sang Mok} and Woo, {Sun Hee} and Cho, {Kwang Hyun}",
year = "2008",
month = "9",
day = "10",
doi = "10.1007/10_2007_093",
language = "English",
isbn = "9783540688174",
series = "Advances in Biochemical Engineering/Biotechnology",
pages = "25--45",
editor = "Meike Werther and Harald Seitz",
booktitle = "Protein - Protein Interaction",

}

Shin, SY, Choo, SM, Woo, SH & Cho, KH 2008, Cardiac systems biology and parameter sensitivity analysis: Intracellular Ca2+ regulatory mechanisms in mouse ventricular myocytes. in M Werther & H Seitz (eds), Protein - Protein Interaction. Advances in Biochemical Engineering/Biotechnology, vol. 110, pp. 25-45. https://doi.org/10.1007/10_2007_093

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 proceedingChapter (Book)Researchpeer-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 -

Shin SY, Choo SM, Woo SH, Cho KH. Cardiac systems biology and parameter sensitivity analysis: Intracellular Ca2+ regulatory mechanisms in mouse ventricular myocytes. In Werther M, Seitz H, editors, Protein - Protein Interaction. 2008. p. 25-45. (Advances in Biochemical Engineering/Biotechnology). https://doi.org/10.1007/10_2007_093