S100A8/A9 aggravates post-ischemic heart failure through activation of RAGE-dependent NF-κB signaling

Basic Res Cardiol. 2012 Mar;107(2):250. doi: 10.1007/s00395-012-0250-z. Epub 2012 Feb 10.


The extracellular heterodimeric protein S100A8/A9 activates the innate immune system through activation of the receptor of advanced glycation end products (RAGE) and Toll-like receptors. As activation of RAGE has recently been associated with sustained myocardial inflammation and heart failure (HF) we studied the role of S100A8/A9 in the development of post-ischemic HF. Hypoxia led to sustained induction of S100A8/A9 accompanied by increased nuclear factor (NF-)κB binding activity and increased expression of pro-inflammatory cytokines in cardiac fibroblasts and macrophages. Knockdown of either S100A8/A9 or RAGE rescued the induction of pro-inflammatory cytokines and NF-κB activation after hypoxia. In a murine model of post-ischemic HF both cardiac RNA and protein levels of S100A8/A9 were elevated as soon as 30 min after hypoxia with sustained activation up to 28 days after ischemic injury. Treatment with recombinant S100A8/A9 resulted in reduced cardiac performance following ischemia/reperfusion. Chimera experiments after bone marrow transplantation demonstrated the importance of RAGE expression on immune cells for their recruitment to the injured myocardium aggravating post-ischemic heart failure. Signaling studies in isolated ventricles indicated that MAP kinases JNK, ERK1/2 as well as NF-κB mediate signals downstream of S100A8/A9-RAGE in post-ischemic heart failure. Interestingly, cardiac performance was not affected by administration of S100A8/A9 in RAGE(-/-)-mice, which demonstrated significantly improved cardiac recovery compared to WT-mice. Our study provides evidence that sustained activation of S100A8/A9 critically contributes to the development of post-ischemic HF driving the progressive course of HF through activation of RAGE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Calgranulin A / metabolism*
  • Calgranulin B / metabolism*
  • Echocardiography
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Heart Failure / etiology
  • Heart Failure / metabolism*
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism*
  • Reperfusion Injury / complications
  • Reperfusion Injury / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Transfection
  • Transplantation Chimera


  • Calgranulin A
  • Calgranulin B
  • NF-kappa B
  • RNA, Small Interfering
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic