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铁离子螯合剂去铁胺上调巨噬细胞、泡沫细胞细胞外基质金属蛋白酶诱导因子表达的机制探讨

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:
2009年第6期
页码:
757-760,769
栏目:
基础研究
出版日期:
2009-11-05

文章信息/Info

Title:
Mechanism of desferrioxamine activity in EMMPRIN expression in macrophages and foam cells
作者:
范虞琪; 何奔; 王彬尧
上海交通大学 医学院附属仁济医院心内科，上海 200001
Author(s):
FAN Yu-qi;  HE Ben;  WANG Bin-yao
Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China
关键词:
去铁胺; 细胞外基质金属蛋白酶诱导因子; 丝裂原活化蛋白激酶; 视黄醛x受体; 动脉粥样硬化
Keywords:
desferrioxamine;  extracellular matrix metalloproteinase inducer;  mitogen-activated protein kinase;  retinoid x receptors;  atherosclerosis
分类号:
Q559
DOI:
-
文献标识码:
A
摘要:
目的: 探讨铁负荷过低上调巨噬细胞、泡沫细胞细胞外基质金属蛋白酶诱导因子(EMMPRIN)表达的机制。研究促分裂原活化的蛋白激酶(MAPK)信号通路、视黄醛x受体（RXR）及过氧化物酶体增殖剂活化受体γ（PPARγ）在此过程中的作用。方法: 将巨噬细胞和泡沫细胞给予MAPK（p38，ERK1/2）信号通路抑制剂及RXR的天然配体预处理，加入或不加入去铁胺继续培养24 h，用Western blot测定细胞中EMMPRIN蛋白的表达。于巨噬细胞和泡沫细胞中加入铁离子鳌合剂去铁胺刺激，用Western blot检测MAPK（p38，ERK1/2）的磷酸化及PPARγ的水平。结果: p38 MAPK通路抑制剂及RXR和配体在本身不影响EMMPRIN表达的同时，可抑制去铁胺对EMMPRIN表达的上调。去铁胺可促进p38 MAPK磷酸化，但不影响PPARγ蛋白表达。结论: p38 MAPK 参与了铁负荷过低上调巨噬细胞和泡沫细胞中EMMPRIN表达的过程；RXR可能参与了该过程。
Abstract:
AIM: To investigate the mechanism of desferrioxamine (DFO) activity on extracellular matrix metalloproteinse inducer(EMMPRIN) expression in macrophages and foam cells. The roles of MAPK pathway, retinoid x receptors (RXR) and nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ) in DFO activity were explored. METHODS: THP-1-derived macrophages and foam cells were pretreated with MAPK (p38, ERK1/2) inhibitors or RXR ligand. The cells were then stimulated with/without DFO for 24 h. EMMPRIN expression, PPARγ expression and the effect of DFO on MAPK phosphorylation were assayed by Western blot. RESULTS: p38 MAPK inhibitor and RXR ligand alone did not modulate EMMPRIN expression but significantly blocked DFO upregulation of EMMPRIN expression. DFO activated p38 MAPK but did not affect PPARγ expression. CONCLUSION: p38 MAPK is involved in iron chelation upregulation of EMMPRIN expression in macrophages and foam cells. RXR may mediate DFO activity.

参考文献/References

［1］ Day SM, Duquaine D, Mundada LV, et al. Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis［J］. Circulation, 2003, 107(20):2601-2606.

［2］ Schmidt R, Bultmann A, Ungerer M, et al. Extracellular matrix metalloproteinase inducer regulates matrix metalloproteinase activity in cardiovascular cells: implications in acute myocardial infarction［J］. Circulation, 2006, 113(6):834-841.

［3］ Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response［J］. Annu Rev Immunol, 2002 20:55-72.

［4］ Huang Z, Wang C, Wei L, et al. Resveratrol inhibits EMMPRIN expression via P38 and ERK1/2 pathways in PMA-induced THP-1 cells［J］. Biochem Biophys Res Commun, 2008, 374(3):517-521.

［5］ Lim M, Martinez T, Jablons D, et al. Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38［J］. FEBS Lett, 1998, 441(1):88-92.

［6］ Claudel T, Leibowitz MD, Fievet C, et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor［J］. Proc Natl Acad Sci U.S.A, 2001, 98(5):2610-2615.

［7］ Lalloyer F, Fievet C, Lestavel S, et al. The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia［J］. Arterioscler Thromb Vasc Biol, 2006, 26(12):2731-2737.

备注/Memo

备注/Memo:
收稿日期：2009-2-25.基金项目：国家自然科学基金项目资助(30670880)；上海市科委基础研究项目资助 (08XD1402600) 通讯作者：王彬尧，教授，主要从事动脉粥样硬化性心脏病防治 研究Email：binyaowang@hotmail.com 作者简介：范虞琪，住院医师，博士生Email：moricizine@gmail.com
更新日期/Last Update: 2009-09-30