title: Leukocyte-Expressed β2-Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury.
abstract: Immune cell-mediated inflammation is an essential process for mounting a repair response after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune system function through β-adrenergic receptors (βARs); however, their role in regulating immune cell responses to acute cardiac injury is unknown.
  
  
  
  Wild-type (WT) mice were irradiated followed by isoform-specific βAR knockout (βARKO) or WT bone-marrow transplantation (BMT) and after full reconstitution underwent MI surgery. Survival was monitored over time, and alterations in immune cell infiltration after MI were examined through immunohistochemistry. Alterations in splenic function were identified through the investigation of altered adhesion receptor expression.
  
  
  
  β2ARKO BMT mice displayed 100% mortality resulting from cardiac rupture within 12 days after MI compared with ≈20% mortality in WT BMT mice. β2ARKO BMT mice displayed severely reduced post-MI cardiac infiltration of leukocytes with reciprocally enhanced splenic retention of the same immune cell populations. Splenic retention of the leukocytes was associated with an increase in vascular cell adhesion molecule-1 expression, which itself was regulated via β-arrestin-dependent β2AR signaling. Furthermore, vascular cell adhesion molecule-1 expression in both mouse and human macrophages was sensitive to β2AR activity, and spleens from human tissue donors treated with β-blocker showed enhanced vascular cell adhesion molecule-1 expression. The impairments in splenic retention and cardiac infiltration of leukocytes after MI were restored to WT levels via lentiviral-mediated re-expression of β2AR in β2ARKO bone marrow before transplantation, which also resulted in post-MI survival rates comparable to those in WT BMT mice.
  
  
  
  Immune cell-expressed β2AR plays an essential role in regulating the early inflammatory repair response to acute myocardial injury by facilitating cardiac leukocyte infiltration.
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Grisanti
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Anna M
authors.initials: AM
authors.lastname: Gumpert
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Traynham
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Gorsky
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Repas
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Carter
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Andrés Pun
authors.initials: AP
authors.lastname: García
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Borja
authors.initials: B
authors.lastname: Ibáñez
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rabinowitz
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.).
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: From Center for Translational Medicine (L.A.G., A.M.G., C.J.T., J.E.G., A.A.R., E.G., R.L.C., J.E.R., W.J.K., D.G.T.), Department of Pharmacology (E.G., J.E.R., W.J.K., D.G.T.), and Department of Clinical Sciences (D.Y.), Temple University School of Medicine, Philadelphia, PA; Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Atlanta, GA (J.W.C.); and Spanish National Center for Cardiovascular Research, Madrid, Spain (A.P.G., B.I.). douglas.tilley@temple.edu.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors / Q000627:therapeutic use; D006341:Heart Rupture / Q000209:etiology*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications*; D020556:Neutrophil Infiltration; D011828:Radiation Chimera; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013156:Splenectomy; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D008790:Metoprolol
keywords: immune system; inflammation; leukocytes; myocardial infarction