Iron overload: what's TIMP-3 got to do with it.
Iron overload: what's TIMP-3 got to do with it.
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铁过载：TIMP-3 与此有何关系。
DOI：
10.1152/ajpheart.00161.2018
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
DeLeon-Pennell,KristineY
中科院分区：
文献类型：
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作者：
Bradshaw,AmyD;DeLeon-Pennell,KristineY
生理学-心脏和循环生理学，Zhabyeyev等人（10）研究了组织金属蛋白酶抑制剂(TIMP)-3在铁超载情况下的作用。慢性铁超载导致体内铁在多个器官系统积聚，包括肝、脾和心脏，对这些器官造成损害。心肌中铁的积累导致铁超载心肌病，这是接受慢性输血治疗的患者死亡的主要原因(4)。在Zhabyeyev等人使用的小鼠模型中，铁超载心肌病与氧化应激、纤维化和舒张功能障碍有关，但不表现为过度炎症或人类铁超载患者典型的收缩功能障碍。因此，在概括人类疾病方面，小鼠模型的一个缺点是缺乏收缩功能障碍成分。有趣的是，与野生型（WT）小鼠相比，铁超载小鼠缺乏TIMP-3表达导致收缩功能降低。TIMP-3在多种细胞类型中表达，包括肝脏中的肝细胞和星状细胞，以及心脏中的肌细胞、中性粒细胞、巨噬细胞、内皮细胞和成纤维细胞(3)。在体内平衡过程中，心脏中TIMP-3的总体水平高于肝脏。在肝脏中，TIMP-3在葡萄糖代谢、肝脏脂肪酸氧化和胆固醇稳态中发挥作用(2)。在心脏，TIMP-3缺失导致16月龄扩张型心肌病。压力过载肥厚的Timp3 J/J小鼠也表现出加速的心脏扩张，通过抑制TNF-α活性和抑制基质金属蛋白酶（MMP）活性来改善心脏扩张(5)。然而，TIMP-3在铁诱导的心肌病中的作用尚不清楚。Zhabyeyev等研究表明，尽管心肌铁超载程度相似，但Timp3 J/J动物与WT小鼠相比，收缩功能下降，舒张功能恶化（10）。Timp3 J/J小鼠的心功能障碍主要归因于纤维化、MMP活性和炎症状态的增加。作者得出结论，TIMP-3在铁诱导的心肌病中具有保护作用，潜在的机制包括调节巨噬细胞从M1到M2表型的分化，减少肝脏中TNF-α的脱落，和/或MMPs作用的衰减。Zhabyeyev等人研究的一个有趣方面（10）是比较在TIMP-3表达缺失的情况下，肝脏和心脏对铁超载的反应，特别是在炎症和MMP表达方面（表1）。虽然Timp3 J/J小鼠铁超载的肝脏中细胞炎症明显增加，并且在Timp3 J/J小鼠中进一步增加，但在WT或Timp3 J/J小鼠铁超载的心脏中均未检测到炎症细胞群的增加。铁超载的心脏中TIMP-3的缺失与TIMP-1和TIMP-2的高表达、明胶酶活性的增加以及与WT小鼠相比纤维化水平的增加有关，这些因素可能导致铁超载的Timp3 J/J小鼠的心功能障碍水平更高。相反，与相应的WT肝脏相比，Timp3 J/J肝脏中大量的中性粒细胞和巨噬细胞与MMP-2、MMP-9或明胶酶活性的显著增加无关。这两种器官的差异反应表明，在心脏中，TIMP-3在调节常驻细胞TIMP和MMP表达方面的作用大于炎症细胞的增加，而在肝脏中，TIMP-3的功能…
Physiology-Heart and Circulatory Physiology, Zhabyeyev et al.(10) investigated the role of tissue inhibitor of metalloproteinase (TIMP)-3 in the setting of iron overload. Chronic iron overload results in excess body iron accumulating in multiple organ systems including the liver, spleen, and heart, causing damage to these organs. Accumulation of iron in the myocardium results in iron overload cardiomyopathy, which is the leading cause of death in patients receiving chronic blood transfusion therapy (4). In murine models such as the one used by Zhabyeyev et al., iron overload cardiomyopathy is associated with oxidative stress, fibrosis, and diastolic dysfunction but does not present with excessive inflammation or with systolic dysfunction typically seen in human patients with iron overload. Hence, one shortcoming of the murine model in terms of recapitulating human disease is a lack of a systolic dysfunction component. Interestingly, the lack of TIMP-3 expression in mice with iron overload resulted in a reduction in systolic function compared with wild-type (WT) mice. TIMP-3 is expressed in multiple cell types including hepatocytes and stellate cells in the liver and in myocytes, neutrophils, macrophages, endothelial cells, and fibroblasts in the heart (3). Overall levels of TIMP-3 are higher in the heart than in the liver during homeostasis. In the liver, TIMP-3 plays a role in glucose metabolism, hepatic fatty acid oxidation, and cholesterol homeostasis (2). In the heart, absence of TIMP-3 results in dilated cardiomyopathy at 16 mo of age. Timp3 J/J mice subjected to pressure overload hypertrophy also exhibit accelerated cardiac dilation, which was ameliorated with inhibition of TNF-α activity and inhibition of matrix metalloproteinase (MMP) activity (5). However, the role of TIMP-3 in iron-induced cardiomyopathy is not well understood. Zhabyeyev et al. showed that despite a similar degree of myocardial iron overload, Timp3 J/J animals had decreased systolic function and worsened diastolic function compared with WT mice (10). Cardiac dysfunction in Timp3 J/J mice was mainly attributed to increased fibrosis, MMP activity, and inflammatory state. The authors concluded that TIMP-3 was protective in iron-induced cardiomyopathy, and potential mechanisms proposed included the modulation of macrophage differentiation from the M1 to M2 phenotype, decreased TNF-α shedding in the liver, and/or attenuation of the actions of MMPs. An interesting aspect of the Zhabyeyev et al. study (10) was the comparison of hepatic versus cardiac response to iron overload in the absence of TIMP-3 expression, particularly in terms of inflammation and MMP expression (Table 1). Although there was a notable increase in cellular inflammation in the iron-overloaded liver that was further increased in Timp3 J/J mice, increases in inflammatory cell populations were not detected in iron-overloaded hearts in either WT or Timp3 J/J mice. The absence of TIMP-3 in the iron-overloaded heart was associated with greater expression of TIMP-1 and TIMP-2, increased gelatinase activity, and increased fibrosis versus levels in WT mice, factors likely contributing to the greater level of cardiac dysfunction in Timp3 J/J mice with iron overload. In contrast, the greater number of neutrophils and macrophages in the Timp3 J/J liver with iron overload was not associated with significant increases in MMP-2, MMP-9, or gelatinase activity compared with corresponding WT liver. The differential response of these two organs suggests that in the heart, TIMP-3 plays a greater role in modulating TIMP and MMP expression by resident cells over that of increases in inflammatory cells, whereas in the liver, the function of …