Attenuation of myocardial injury by HMGB1 blockade during ischemia/reperfusion is toll-like receptor 2-dependent

Mediators Inflamm. 2013:2013:174168. doi: 10.1155/2013/174168. Epub 2013 Nov 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Female
  • HMGB1 Protein / antagonists & inhibitors
  • HMGB1 Protein / genetics
  • HMGB1 Protein / physiology*
  • Humans
  • Leukocytes / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Myocardial Reperfusion Injury / prevention & control*
  • Polymorphism, Genetic
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / physiology
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / physiology*
  • Troponin T / blood

Substances

  • HMGB1 Protein
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Toll-Like Receptor 2
  • Troponin T