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

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.

Angiotensin II regulates phosphorylation of actin‐associated proteins in human podocytes

“…Temporal dynamics of phosphorylation events upon GPCR activation are highly complex (31)(32)(33); therefore, we performed time course experiments and demonstrated the phosphorylation of ERK within the first 15 min after AngII stimulation (14). Thus, we chose this time point for our proteomic study.…”

Interplay between the E2F pathway and β-adrenergic signaling in the pathological hypertrophic response of myocardium

“…c-Src/ERK has been demonstrated to activate a survival signal through up regulation of the anti-apoptotic/survival protein, Bcl2 [27]. Western blot examination of Bcl2 revealed a single polypeptidẽ 26 kDa which was barely detectable in Wt myocardium, but was induced~100 fold by E2F6 expression (p-value: 0.00001) (Fig.…”

Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

“…These investigators combined experimental measurements with simulations to uncover mechanisms by which high and sustained doses of the β-adrenergic receptor agonist isoproterenol could increase myocyte susceptibility to apoptosis (Shin et al, 2014). This study is an important example of how simulations often generate novel experimentally-testable predictions, and the work can potentially be extended to examine TKI-induced toxicity.…”

“…For instance, cell death via apoptosis, which may be important in the development of toxicity caused by some TKIs, has been described mathematically by many previous models (Schleich and Lavrik, 2013;Shin et al, 2014). Once these are tuned to reflect apoptotic signaling in cardiac myocytes, the models can be integrated with the experimental gene expression data to generate novel predictions.…”

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