Short-term β-adrenergic stimulation promotes contractility in response to stress but is ultimately detrimental in the failing heart because of accrual of cardiomyocyte death. Endogenous cardiac progenitor cell (CPC) activation may partially offset cardiomyocyte losses, but consequences of long-term β-adrenergic drive on CPC survival and proliferation are unknown.We sought to determine the relationship between β-adrenergic activity and regulation of CPC function.Mouse and human CPCs express only β2 adrenergic receptor (β2-AR) in conjunction with stem cell marker c-kit. Activation of β2-AR signaling promotes proliferation associated with increased AKT, extracellular signal-regulated kinase 1/2, and endothelial NO synthase phosphorylation, upregulation of cyclin D1, and decreased levels of G protein-coupled receptor kinase 2. Conversely, silencing of β2-AR expression or treatment with β2-antagonist ICI 118, 551 impairs CPC proliferation and survival. β1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by metoprolol. Efficacy of β1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed in vivo by adoptive transfer of CPC into failing mouse myocardium.β-adrenergic stimulation promotes expansion and survival of CPCs through β2-AR, but acquisition of β1-AR on commitment to the myocyte lineage results in loss of CPCs and early myocyte precursors.

β-Adrenergic regulation of cardiac progenitor cell death versus survival and proliferation / M., Khan; S., Mohsin; Avitabile, Daniele; S., Siddiqi; J., Nguyen; K., Wallach; P., Quijada; M., Mcgregor; N., Gude; R., Alvarez; D. G., Tilley; W. J., Koch; M. A., Sussman. - In: CIRCULATION RESEARCH. - ISSN 0009-7330. - 112:(2013), pp. 476-486. [10.1161/CIRCRESAHA.112.280735]

β-Adrenergic regulation of cardiac progenitor cell death versus survival and proliferation.

AVITABILE, DANIELE;
2013

Abstract

Short-term β-adrenergic stimulation promotes contractility in response to stress but is ultimately detrimental in the failing heart because of accrual of cardiomyocyte death. Endogenous cardiac progenitor cell (CPC) activation may partially offset cardiomyocyte losses, but consequences of long-term β-adrenergic drive on CPC survival and proliferation are unknown.We sought to determine the relationship between β-adrenergic activity and regulation of CPC function.Mouse and human CPCs express only β2 adrenergic receptor (β2-AR) in conjunction with stem cell marker c-kit. Activation of β2-AR signaling promotes proliferation associated with increased AKT, extracellular signal-regulated kinase 1/2, and endothelial NO synthase phosphorylation, upregulation of cyclin D1, and decreased levels of G protein-coupled receptor kinase 2. Conversely, silencing of β2-AR expression or treatment with β2-antagonist ICI 118, 551 impairs CPC proliferation and survival. β1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by metoprolol. Efficacy of β1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed in vivo by adoptive transfer of CPC into failing mouse myocardium.β-adrenergic stimulation promotes expansion and survival of CPCs through β2-AR, but acquisition of β1-AR on commitment to the myocyte lineage results in loss of CPCs and early myocyte precursors.
2013
Adrenergic beta-2 Receptor Agonists; pharmacology, Adrenergic beta-2 Receptor Antagonists; pharmacology, Animals, Cell Death, Cell Proliferation; drug effects, Cell Survival, Cells; Cultured, Coculture Techniques, Cyclin D1; metabolism, Disease Models; Animal, Dose-Response Relationship; Drug, G-Protein-Coupled Receptor Kinase 2; metabolism, Humans, Male, Mice, Mitogen-Activated Protein Kinase 1; metabolism, Mitogen-Activated Protein Kinase 3; metabolism, Myocardial Infarction; metabolism/pathology/surgery, Myocytes; Cardiac; drug effects/metabolism/pathology/transplantation, Nitric Oxide Synthase Type III; metabolism, Phosphorylation, Proto-Oncogene Proteins c-akt; metabolism, Proto-Oncogene Proteins c-kit; metabolism, RNA Interference, Receptors; Adrenergic; beta-1; drug effects/genetics/metabolism, Receptors; beta-2; drug effects/genetics/metabolism, Signal Transduction; drug effects, Stem Cell Transplantation, Stem Cells; drug effects/metabolism/pathology, Time Factors, Transfection
01 Pubblicazione su rivista::01a Articolo in rivista
β-Adrenergic regulation of cardiac progenitor cell death versus survival and proliferation / M., Khan; S., Mohsin; Avitabile, Daniele; S., Siddiqi; J., Nguyen; K., Wallach; P., Quijada; M., Mcgregor; N., Gude; R., Alvarez; D. G., Tilley; W. J., Koch; M. A., Sussman. - In: CIRCULATION RESEARCH. - ISSN 0009-7330. - 112:(2013), pp. 476-486. [10.1161/CIRCRESAHA.112.280735]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/739601
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