title: β-Adrenergic regulation of cardiac progenitor cell death versus survival and proliferation.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We sought to determine the relationship between β-adrenergic activity and regulation of CPC function.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: San Diego Heart Research Institute, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitabile
authors.forename: Sailay
authors.initials: S
authors.lastname: Siddiqi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nguyen
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wallach
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.forename: Michael
authors.initials: M
authors.lastname: McGregor
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.forename: Roberto
authors.initials: R
authors.lastname: Alvarez
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D034622:RNA Interference; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection
chemical_list: C553443:ADRB2 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D019938:Cyclin D1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; C496567:GRK2 protein, human; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; C535150:MAPK1 protein, human; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3