Metallothioneins 1 and 2 Modulate Inflammation and Support Remodeling in Ischemic Cardiomyopathy in Mice.
Metallothioneins 1 and 2 Modulate Inflammation and Support Remodeling in Ischemic Cardiomyopathy in Mice.
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DOI：
10.1155/2016/7174127
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发表时间：
2016
影响因子：
4.6
通讯作者：
Dewald O
中科院分区：
文献类型：
--
作者：
Duerr GD;Dewald D;Schmitz EJ;Verfuerth L;Keppel K;Peigney C;Ghanem A;Welz A;Dewald O
目标。反复短暂缺血再灌注（I/R）与缺血性心肌病发生过程中的左室功能障碍有关。我们研究了锌供体蛋白MT 1和MT 2在闭胸小鼠I/R模型中的作用。方法.在SV 129（WT）和MT 1/2（MT-/-）敲除小鼠（n = 8-10/组）中，每天进行15分钟LAD闭塞，持续1、3和7天。用M型超声心动图检查心脏，并进行组织学和mRNA研究。结果WT-小鼠反复I/R过程中MT 1/2 mRNA的表达被瞬时诱导，伴随短暂的炎症反应，导致间质纤维化伴左心室功能障碍而无梗死。相比之下，MT−/−-心脏表现为细胞凋亡增强和小梗死，导致整体和局部泵功能受损。分子分析揭示了MT 1/2−/−-心脏中肌球蛋白重链亚型和抗氧化酶的适应不良。尽管他们推迟了趋化因子的诱导，我们发现MT−/−-心脏的小梗死灶中总的中性粒细胞密度和巨噬细胞浸润较高。随后，骨桥蛋白1和腱生蛋白C的高表达与肌成纤维细胞密度增加相关，导致MT 1/2−/−-心脏主要不可逆的纤维化和不良重塑。结论MT 1/2的心肌保护作用似乎是通过调节收缩因子、抗氧化酶、炎症反应和心肌重塑来发挥的。
Aims. Repetitive brief ischemia and reperfusion (I/R) is associated with left ventricular dysfunction during development of ischemic cardiomyopathy. We investigated the role of zinc-donor proteins metallothionein MT1 and MT2 in a closed-chest murine model of I/R. Methods. Daily 15-minute LAD-occlusion was performed for 1, 3, and 7 days in SV129 (WT)- and MT1/2 knockout (MT−/−)-mice (n = 8–10/group). Hearts were examined with M-mode echocardiography and processed for histological and mRNA studies. Results. Expression of MT1/2 mRNA was transiently induced during repetitive I/R in WT-mice, accompanied by a transient inflammation, leading to interstitial fibrosis with left ventricular dysfunction without infarction. In contrast, MT−/−-hearts presented with enhanced apoptosis and small infarctions leading to impaired global and regional pump function. Molecular analysis revealed maladaptation of myosin heavy chain isoforms and antioxidative enzymes in MT1/2−/−-hearts. Despite their postponed chemokine induction we found a higher total neutrophil density and macrophage infiltration in small infarctions in MT−/−-hearts. Subsequently, higher expression of osteopontin 1 and tenascin C was associated with increased myofibroblast density resulting in predominately nonreversible fibrosis and adverse remodeling in MT1/2−/−-hearts. Conclusion. Cardioprotective effects of MT1/2 seem to be exerted via modulation of contractile elements, antioxidative enzymes, inflammatory response, and myocardial remodeling.