title: Preconditioning by toll-like receptor 2 agonist Pam3CSK4 reduces CXCL1-dependent leukocyte recruitment in murine myocardial ischemia/reperfusion injury.
abstract: OBJECTIVE
  To test whether preconditioning with a toll-like receptor (TLR) 2 agonist protects against myocardial ischemia and reperfusion by interfering with chemokine CXCL1 release from cardiomyocytes.
  
  
  METHODS
  C3H mice were challenged with vehicle or synthetic TLR2 agonist Pam3Cys-Ser-Lys4 (Pam3CSK4; 1 mg/kg) 24 hrs before myocardial ischemia (20 mins) and reperfusion (2 hrs or 24 hrs). Infarct size, troponin T release, and leukocyte recruitment were quantified. In murine cardiomyocytes (HL-1), we studied the expression/activation profile of TLR2 in response to stimulation with Pam3CSK4 (0.01-1 mg/mL). Furthermore, we studied the chemokine ligand 1 (CXCL1) response to Pam3CSK4 and ischemia/reperfusion in vivo and in vitro.
  
  
  METHODS
  University hospital research laboratory.
  
  
  METHODS
  Anesthetized male mice and murine cardiomyocytes.
  
  
  RESULTS
  Preconditioning by Pam3CSK4 reduced infarct size and troponin T release. This was accompanied by a decreased recruitment of leukocytes into the ischemic area and an improved cardiac function. In HL-1 cells, TLR2 activation amplified the expression of the receptor in a time-dependent manner and led to CXCL1 release in a concentration-dependent manner. Preconditioning by Pam3CSK4 impaired CXCL1 release in response to a second inflammatory stimulus in vivo and in vitro.
  
  
  CONCLUSIONS
  Preconditioning by TLR2 agonist Pam3CSK4 reduces myocardial infarct size after myocardial ischemia/reperfusion. One of the mechanisms involved is a diminished chemokine release from cardiomyocytes, which subsequently limits leukocyte infiltration.
authors.affiliation: Clinic of Anesthesiology, Intensive Care Medicine, and Pain Management, JW Goethe University, Frankfurt, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Mersmann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Berkels
authors.forename: Paula
authors.initials: P
authors.lastname: Zacharowski
authors.forename: Nguyen
authors.initials: N
authors.lastname: Tran
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Kazuma
authors.initials: K
authors.lastname: Iekushi
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Granja
authors.forename: Olaf
authors.initials: O
authors.lastname: Boehm
authors.forename: William C
authors.initials: WC
authors.lastname: Claycomb
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
mesh_terms: D000818:Animals; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019157:Ischemic Preconditioning, Myocardial; D007962:Leukocytes / Q000276:immunology*; D055666:Lipopeptides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009203:Myocardial Infarction / Q000276:immunology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000276:immunology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics*; D020107:Troponin T / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; D018925:Chemokines; C475895:Cxcl1 protein, mouse; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D020107:Troponin T