The switching role of β-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 25517116.
- Also identified by DOI 10.1038/ncomms6777 and PMC identifier 4284638.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 β-adrenergic receptor (β-AR) stimulation. Mathematical simulations combined with biochemical experimentation of β-AR signalling pathways show that the gradual increment of isoproterenol (a non-selective β1/β2-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 β1-blocker treatment increases the survival effect of β-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.
Medical subject headings
- Cyclic AMP Response Element Modulator
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- Myocytes, Cardiac
- Receptors, Adrenergic, beta-1
- Receptors, Adrenergic, beta-2
- Signal Transduction