title: Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice.
abstract: OBJECTIVE
  Reperfusion ofmyocardial infarction is associated with inflammatory reaction and subsequentmyocardial remodeling with a rapid scar formation in mice. The cannabinoid receptor CB2 has been associated with cardioprotection and regulation ofmacrophage function.Weinvestigated its role in remodeling of reperfused infarction.
  
  
  METHODS
  One hour LAD-occlusion was followed by reperfusion over 6 h and 1, 3 and 7 days in wild-type C57/BL6J (WT) and CB2 receptor-deficient (Cnr2−/−)mice (n=8/group). Hearts were processed for functional, morphological and mRNA/protein analysis, and tissue concentration of endocannabinoidswas determined using liquid chromatography-multiple reaction monitoring.
  
  
  RESULTS
  In contrast to a rapid formation of granulation tissue and a compacted non-transmural scar inWT mice after 7 days of reperfusion, Cnr2−/− mice showed a non-compacted transmural scar. Millar® left ventricular catheter measurements revealed a significantly worse function in Cnr2−/− mice.We found no compensatory elevation of endocannabinoid concentration in Cnr2−/− hearts. Macrophage infiltration was significantly stronger in Cnr2−/− hearts and affected also the remote septum, when compared to WT hearts.We found a cytokine-driven inflammatory response in Cnr2−/− hearts with no significant induction of chemokines. Immunohistochemistry for thrombospondin-1 revealed a dysfunctional infarction border zone formation in Cnr2−/− hearts. Cnr2−/−hearts showed no significant induction of tenascin C, collagen-Iα or lysil oxidase, thereby indicating adversemyocardial remodeling.
  
  
  CONCLUSIONS
  Endocannabinoids act via CB2 receptor in the modulation of inflammatory response and myocardial remodeling after infarction. CB2 receptor plays an important role in the formation of infarction border zone, collagen deposition and organization of stable scar during remodeling.
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Georg D
authors.initials: GD
authors.lastname: Duerr
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Heinemann
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gestrich
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Heuft
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Klaas
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Keppel
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Roell
authors.affiliation: Institute of Physiology I, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Klein
authors.affiliation: Institute of Molecular Psychiatry, Life & Brain Center, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: Department of Anesthesiology, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Velten
authors.affiliation: Institute of Pharmacology and Toxicology, Biomedical Center, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Kilic
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Bindila
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Electronic address: o.dewald@uni-bonn.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dewald
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006097:Granulation Tissue / Q000473:pathology; D006439:Hemodynamics; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D043885:Receptor, Cannabinoid, CB2 / Q000172:deficiency* / Q000235:genetics*
chemical_list: C571431:Cnr2 protein, mouse; D016207:Cytokines; D043885:Receptor, Cannabinoid, CB2
keywords: Endocannabinoids; Infarction border zone; Ischemia; Reperfusion; Thrombospondin