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Published on: May 31, 2018
Iron deficiency activates pro-inflammatory signaling in macrophages and foam cells via the p38 MAPK-NF-κB pathway
1Department of Cardiology, Renji Hospital, Shanghai Jiaotong University Medical School, 145 Middle Shandong Road, Shanghai 200001, PR China.
Insights
Iron deficiency exacerbates inflammation in atherosclerotic plaques by activating the p38 MAPK-NF-κB-EMMPRIN/MMP-9 pathway. This finding explains how bleeding in acute coronary syndrome patients may lead to recurrent events and mortality.
Area of Science:
- Cardiovascular Research
- Inflammation and Immunology
- Atherosclerosis Pathogenesis
Background:
- Major bleeding in acute coronary syndrome (ACS) patients is linked to increased recurrent ACS and mortality.
- The underlying mechanisms connecting bleeding, iron deficiency, and adverse cardiovascular outcomes remain unclear.
- Iron deficiency is known to promote inflammation in various disease states.
Purpose of the Study:
- To investigate the specific impact of iron deficiency on atherosclerotic plaque destabilization.
- To elucidate the pro-inflammatory role of iron deficiency in atheroma.
- To identify the molecular pathways involved in iron deficiency-induced plaque inflammation.
Main Methods:
- Assessed mRNA levels of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) and Matrix Metalloproteinase-9 (MMP-9) via RT-PCR.
- Quantified protein levels of EMMPRIN, MMP-9, Nuclear Factor-kappa B (NF-κB)-p65, and Peroxisome Proliferator-Activated Receptor gamma (PPARγ) using western blotting.
- Measured MMP-9 enzymatic activity through gelatin zymography and analyzed Mitogen-Activated Protein Kinase (MAPK) phosphorylation.
Main Results:
- Iron deficiency increased EMMPRIN and MMP-9 production and activity in macrophages and foam cells.
- Iron deficiency activated NF-κB and p38 MAPK signaling pathways.
- Inhibition studies confirmed that p38 MAPK and NF-κB activation are crucial for iron deficiency-induced EMMPRIN and MMP-9 upregulation.
- PPARγ activation did not prevent the pro-inflammatory effects; iron deficiency did not alter PPARγ expression.
- Retinoid X receptor agonist partially reversed iron deficiency's effects on EMMPRIN, MMP-9, and NF-κB, but not MAPK activation.
Conclusions:
- Iron deficiency promotes atheroma inflammation via the p38 MAPK-NF-κB-EMMPRIN/MMP-9 signaling cascade.
- These findings offer a potential mechanistic link between major bleeding, subsequent iron deficiency, and adverse outcomes in ACS patients.
- Understanding this pathway may inform therapeutic strategies to mitigate risks associated with bleeding in ACS.
Background/Objectives:
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.
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