title: Differential Tissue-Specific Function of Adora2b in Cardioprotection.
abstract: The adenosine A2b receptor (Adora2b) has been implicated in cardioprotection from myocardial ischemia. As such, Adora2b was found to be critical in ischemic preconditioning (IP) or ischemia/reperfusion (IR) injury of the heart. Whereas Adora2b is present on various cells types, the tissue-specific role of Adora2b in cardioprotection is still unknown. To study the tissue-specific role of Adora2b signaling on inflammatory cells, endothelia, or myocytes during myocardial ischemia in vivo, we intercrossed floxed Adora2b mice with Lyz2-Cre(+), VE-cadherin-Cre(+), or myosin-Cre(+) transgenic mice, respectively. Mice were exposed to 60 min of myocardial ischemia with or without IP (four times for 5 min) followed by 120 min of reperfusion. Cardioprotection by IP was abolished in Adora2b(f/f)-VE-cadherin-Cre(+) or Adora2b(f/f)-myosin-Cre(+), indicating that Adora2b signaling on endothelia or myocytes mediates IP. In contrast, primarily Adora2b signaling on inflammatory cells was necessary to provide cardioprotection in IR injury, indicated by significantly larger infarcts and higher troponin levels in Adora2b(f/f)-Lyz2-Cre(+) mice only. Cytokine profiling of IR injury in Adora2b(f/f)-Lyz2-Cre(+) mice pointed toward polymorphonuclear neutrophils (PMNs). Analysis of PMNs from Adora2b(f/f)-Lyz2-Cre(+) confirmed PMNs as one source of identified tissue cytokines. Finally, adoptive transfer of Adora2b(-/-) PMNs revealed a critical role of Adora2b on PMNs in cardioprotection from IR injury. Adora2b signaling mediates different types of cardioprotection in a tissue-specific manner. These findings have implications for the use of Adora2b agonists in the treatment or prevention of myocardial injury by ischemia.
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045; Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Seong-wook
authors.initials: SW
authors.lastname: Seo
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045; Department of Anesthesiology, Ludwig Maximilians University Munich, 80336 Munich, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Koeppen
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bonney
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045;
authors.forename: Merit
authors.initials: M
authors.lastname: Gobel
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045;
authors.forename: Molly
authors.initials: M
authors.lastname: Thayer
authors.affiliation: Institute of Neurology (Edinger Institute), University of Frankfurt, 60528 Frankfurt, Germany;
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118; and.
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045;
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.affiliation: Institute of Neurology (Edinger Institute), University of Frankfurt, 60528 Frankfurt, Germany;
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Division of Cardiology, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Lori
authors.initials: L
authors.lastname: Walker
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045; tobias.eckle@ucdenver.edu.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eckle
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D004195:Disease Models, Animal; D004727:Endothelium / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D009928:Organ Specificity / Q000235:genetics; D043704:Receptor, Adenosine A2B / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D043704:Receptor, Adenosine A2B