Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice.
Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice.
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四甲酸氢酶铜螯合会抑制载脂蛋白E缺陷小鼠的血管炎症和动脉粥样硬化病变的发育。
DOI：
10.1016/j.atherosclerosis.2012.06.013
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发表时间：
2012-08
期刊：
影响因子：
5.3
通讯作者：
Frei, Balz
中科院分区：
文献类型：
--
作者：
Wei, Hao;Zhang, Wei-Jian;McMillen, Timothy S.;LeBoeuf, Renee C.;Frei, Balz
以细胞粘附分子、促炎趋化因子和细胞因子的上调为特征的内皮活化以及随后的单核细胞向动脉内膜的募集是动脉粥样硬化的病因学因素。氧化还原活性的过渡金属离子，如铜和铁，可能通过刺激氧化还原敏感的细胞信号通路在内皮活化中发挥重要作用。我们以前已经表明，铜螯合四硫代钼酸盐（TTM）抑制LPS诱导的急性炎症反应在体内。在这里，我们研究TTM是否可以抑制载脂蛋白E缺陷（apoE−/−）小鼠动脉粥样硬化病变的发展。我们发现，用TTM（饮食中33-66 ppm）对apoE−/−小鼠进行10周治疗，使血清含铜蛋白铜蓝蛋白水平降低47%，血清铁水平降低26%。组织水平的“生物可利用”铜，铜钼比评估，降低了80%，在主动脉和心脏，而铁的这些组织的水平没有受到TTM治疗。此外，与未接受TTM治疗的apoE−/−小鼠相比，TTM显著减少了25%的全主动脉和45%的降主动脉粥样硬化病变。TTM的这种抗动脉粥样硬化作用伴随着几种抗炎作用，即，显著降低可溶性血管细胞和细胞间粘附分子（VCAM-1和ICAM-1）的血清水平;降低VCAM-1、ICAM-1、单核细胞趋化蛋白-1和促炎细胞因子的主动脉基因表达;以及显著减少M1型巨噬细胞的主动脉蓄积。与此相反，血清氧化低密度脂蛋白水平没有降低TTM。这些数据表明，TTM通过减少生物可利用的铜和血管炎症来抑制apoE−/−小鼠的动脉粥样硬化，而不是通过改变铁稳态或减少氧化应激。
Endothelial activation, which is characterized by upregulation of cellular adhesion molecules and pro-inflammatory chemokines and cytokines, and consequent monocyte recruitment to the arterial intima are etiologic factors in atherosclerosis. Redox-active transition metal ions, such as copper and iron, may play an important role in endothelial activation by stimulating redox-sensitive cell signaling pathways. We have shown previously that copper chelation by tetrathiomolybdate (TTM) inhibits LPS-induced acute inflammatory responses in vivo. Here, we investigated whether TTM can inhibit atherosclerotic lesion development in apolipoprotein E-deficient (apoE−/−) mice. We found that 10-week treatment of apoE−/− mice with TTM (33–66 ppm in the diet) reduced serum levels of the copper-containing protein, ceruloplasmin, by 47%, and serum iron by 26%. Tissue levels of “bioavailable” copper, assessed by the copper-to-molybdenum ratio, decreased by 80% in aorta and heart, whereas iron levels of these tissues were not affected by TTM treatment. Furthermore, TTM significantly attenuated atherosclerotic lesion development in whole aorta by 25% and descending aorta by 45% compared to non-TTM treated apoE−/− mice. This anti-atherogenic effect of TTM was accompanied by several anti-inflammatory effects, i.e., significantly decreased serum levels of soluble vascular cell and intercellular adhesion molecules (VCAM-1 and ICAM-1); reduced aortic gene expression of VCAM-1, ICAM-1, monocyte chemotactic protein-1, and pro-inflammatory cytokines; and significantly less aortic accumulation of M1 type macrophages. In contrast, serum levels of oxidized LDL were not reduced by TTM. These data indicate that TTM inhibits atherosclerosis in apoE−/− mice by reducing bioavailable copper and vascular inflammation, not by altering iron homeostasis or reducing oxidative stress.
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影响因子：
4.2
作者：
BABU, U;FAILLA, ML
通讯作者：
FAILLA, ML
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