title: Attenuation of myocardial injury by HMGB1 blockade during ischemia/reperfusion is toll-like receptor 2-dependent.
abstract: Genetic or pharmacological ablation of toll-like receptor 2 (TLR2) protects against myocardial ischemia/reperfusion injury (MI/R). However, the endogenous ligand responsible for TLR2 activation has not yet been detected. The objective of this study was to identify HMGB1 as an activator of TLR2 signalling during MI/R. C57BL/6 wild-type (WT) or TLR2(-/-)-mice were injected with vehicle, HMGB1, or HMGB1 BoxA one hour before myocardial ischemia (30 min) and reperfusion (24 hrs). Infarct size, cardiac troponin T, leukocyte infiltration, HMGB1 release, TLR4-, TLR9-, and RAGE-expression were quantified. HMGB1 plasma levels were measured in patients undergoing coronary artery bypass graft (CABG) surgery. HMGB1 antagonist BoxA reduced cardiomyocyte necrosis during MI/R in WT mice, accompanied by reduced leukocyte infiltration. Injection of HMGB1 did, however, not increase infarct size in WT animals. In TLR2(-/-)-hearts, neither BoxA nor HMGB1 affected infarct size. No differences in RAGE and TLR9 expression could be detected, while TLR2(-/-)-mice display increased TLR4 and HMGB1 expression. Plasma levels of HMGB1 were increased MI/R in TLR2(-/-)-mice after CABG surgery in patients carrying a TLR2 polymorphism (Arg753Gln). We here provide evidence that absence of TLR2 signalling abrogates infarct-sparing effects of HMGB1 blockade.
authors.affiliation: Department of Anaesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Mersmann
authors.affiliation: Department of Anaesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Iskandar
authors.affiliation: Department of Anaesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Kathrina
authors.initials: K
authors.lastname: Latsch
authors.affiliation: Department of Anaesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Habeck
authors.affiliation: Department of Anaesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Sprunck
authors.affiliation: Department of Anaesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany ; Department of Trauma Surgery, University Hospital Gießen and Marburg GmbH, 35043 Marburg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Zimmermann
authors.affiliation: Institute for Microbiology and Hygiene, Charité Medical Center, 12203 Berlin, Germany.
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.affiliation: Department of Anaesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.affiliation: Department of Anaesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011110:Polymorphism, Genetic; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology*; D020107:Troponin T / Q000097:blood
chemical_list: D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D020107:Troponin T