title: Iron deficiency activates pro-inflammatory signaling in macrophages and foam cells via the p38 MAPK-NF-κB pathway.
abstract: OBJECTIVE
  Major bleeding in patients with acute coronary syndrome (ACS) increases the risk of recurrent ACS and mortality. However, the mechanism involved is poorly understood. Bleeding induces iron deficiency. Iron deficiency enhances inflammation in other diseases. Thus, in this paper, the particular effect of iron deficiency on atherosclerotic plaque destabilization, especially the pro-inflammatory role of iron deficiency in atheroma and the mechanism involved were investigated.
  
  
  METHODS
  Extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 (MMP-9) mRNA levels were investigated by RT-PCR. EMMPRIN and MMP-9 protein levels, nuclear factor (NF)-κB-p65 protein levels, peroxisome proliferator-activated receptor γ (PPARγ) protein levels, and mitogen-activated protein kinase (MAPK) phosphorylation were determined by western blotting. MMP-9 enzymatic activity was assayed by gelatin zymography.
  
  
  RESULTS
  Iron deficiency enhanced EMMPRIN, MMP-9 production, and MMP-9 enzymatic activity in THP-1 derived macrophages and foam cells. Iron deficiency elicited the activation of NF-κB and p38 MAPK. By using the p38 inhibitor and NF-κB inhibitor, the study established that EMMPRIN and MMP-9 inductions by iron deficiency required the consecutive upstream activation of p38 MAPK and NF-κB. This pro-inflammatory action was not prevented by PPARγ agonist. Meanwhile, iron deficiency did not modulate PPARγ expression. Retinoid X receptor agonist suppressed the effects of iron deficiency on EMMPRIN , MMP-9, and NF-κB, but not on MAPK activation.
  
  
  CONCLUSIONS
  Iron deficiency enhances atheroma inflammation through p38 MAPK-NF-κB-EMMPRIN/MMP-9 pathway. Our findings provide a potential mechanism for the association of major bleeding with recurrent ACS and mortality in patients with ACS.
authors.affiliation: Department of Cardiology, Renji Hospital, Shanghai Jiaotong University Medical School, 145 Middle Shandong Road, Shanghai 200001, PR China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Fan
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Wei
authors.forename: Ben
authors.initials: B
authors.lastname: He
authors.forename: Changqian
authors.initials: C
authors.lastname: Wang
authors.forename: Binyao
authors.initials: B
authors.lastname: Wang
mesh_terms: D054058:Acute Coronary Syndrome / Q000276:immunology* / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism; D051926:Basigin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003676:Deferoxamine / Q000494:pharmacology; D005487:Foam Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006470:Hemorrhage / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000276:immunology; D000090463:Iron Deficiencies; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: C497886:BSG protein, human; D017262:Siderophores; D051996:Transcription Factor RelA; D051926:Basigin; D007501:Iron; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D003676:Deferoxamine