Int J Cardiol 2011 Oct;152 (1): 49-55. [IF:6.802]
Iron deficiency activates pro-inflammatory signaling in macrophages and foam
cells via the p38 MAPK-NF-κB pathway.
Fan Y , Wang J , Wei L , He B , Wang C , Wang B .
Department of Cardiology, Renji Hospital, Shanghai Jiaotong University Medical School, 145 Middle Shandong Road, Shanghai 200001, PR China.
上海交通大学医学院附属仁济医院心内科
Abstract
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. 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. 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. 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.
摘要
急性冠脉综合征患者大出血增加了急性冠脉综合症的再发及死亡的危险性。然而，相关机制未充分理解。出血导致铁缺乏。铁缺乏增加其他疾病的炎症。 因此，在该论文中铁缺乏对于动脉粥样硬化斑块不稳定性的特殊效应，尤其是铁缺乏在粥样斑块中得促炎作用和相关机制进行了研究。通过实时PCR对细胞外基质金属蛋白酶和基质金属蛋白酶-9的信使RNA水平进行了研究。 由蛋白印迹确定细胞外基质金属蛋白酶和基质金属蛋白酶-9水平，NF-κB-p65蛋白水平，过氧化物酶体增生物激活受体水平，和促分裂原活化蛋白激酶磷酸化水平。通过明胶酶谱法测定基质金属蛋白酶-9的酶活性。铁缺乏增加细胞外基质金属蛋白酶和基质金属蛋白酶-9含量和基质金属蛋白酶在巨噬细胞和泡沫细胞来源的单核细胞中的酶活性。 铁缺乏引发NF-κB 和 p38促分裂原活化蛋白激酶的活性。通过P38抑制剂和NF-κB 抑制剂，该研究通过铁缺乏进行了细胞外基质金属蛋白酶和基质金属蛋白酶-9的诱导，而铁缺乏需要对p38 MAPK和NF-κB进行连续性上调活化。该促炎活性并不被过氧化物酶体增生物激活受体γ激动剂所抑制。同时，铁缺乏并不调节过氧化物酶体增生物激活受体γ表达。视黄醇类X受体激动剂抑制铁缺乏对于细胞外基质金属蛋白酶和基质金属蛋白酶-9，和NF-κB 的效应，但并不抑制促分裂原活化蛋白激酶活性。 铁缺乏通过p38 MAPK-NF-κB-EMMPRIN/MMP-9通路增强动脉粥样斑块炎症。我们的研究结果为复发性冠脉综合症的大出血和急性冠脉综合症患者的死亡的联系提供了可能的机制。
