title: 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.
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
authors.forename: Sung-Young
authors.initials: SY
authors.lastname: Shin
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Korea.
authors.forename: Taeyong
authors.initials: T
authors.lastname: Kim
authors.affiliation: 1] Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea [2] Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Korea.
authors.forename: Ho-Sung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: 1] Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea [2] Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Korea.
authors.forename: Jun Hyuk
authors.initials: JH
authors.lastname: Kang
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: 1] Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea [2] Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Korea.
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Cho
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Korea.
authors.forename: Do Han
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D061251:Primary Cell Culture; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000318:Adrenergic beta-Agonists; C497412:Crem protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D051786:Cyclic AMP Response Element Modulator; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D007545:Isoproterenol