The switching role of i 2-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes

Sung Young Shin, Taeyong Kim, Ho Sung Lee, Jun Hyuk Kang, Ji Young Lee, Kwang Hyun Cho, Do Han Kim

Research output: Contribution to journalArticleResearchpeer-review

31 Citations (Scopus)

Abstract

How cell fate (survival or death) is determined and whether such determination depends on the strength of stimulation has remained unclear. In this study, we discover that the cell fate of cardiomyocytes switches from survival to death with the increase of I 2-adrenergic receptor (I 2-AR) stimulation. Mathematical simulations combined with biochemical experimentation of I 2-AR signalling pathways show that the gradual increment of isoproterenol (a non-selective I 2 1 /I 2 2 -AR agonist) induces the switching response of Bcl-2 expression from the initial increase followed by a decrease below its basal level. The ERK1/2 and ICER-mediated feed-forward loop is the hidden design principle underlying such cell fate switching characteristics. Moreover, we find that I 21-blocker treatment increases the survival effect of I 2-AR stimuli through the regulation of Bcl-2 expression leading to the resistance to cell death, providing new insight into the mechanism of therapeutic effects. Our systems analysis further suggests a novel potential therapeutic strategy for heart disease.

Original languageEnglish
Article number5777
Number of pages13
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 17 Dec 2014
Externally publishedYes

Keywords

  • cardiovascular diseases
  • cell death
  • cell signalling

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