ADAMTS13 safeguards the myocardium in a mouse model of acute myocardial infarction.
ADAMTS13 safeguards the myocardium in a mouse model of acute myocardial infarction.
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ADAMTS13 可保护急性心肌梗死小鼠模型中的心肌。
DOI：
10.1160/th12-09-0674
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
and Mitsuhiko Sugimoto.
中科院分区：
文献类型：
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作者：
Masaaki Doi;Hideto Matsui;Yukiji Takeda;Yoshihiko Saito;Maiko Takeda;Yasunori Matsunari;Kenji Nishio;Midori Shima;Fumiaki Banno;Masashi Akiyama;Koichi Kokame;Toshiyuki Miyata;and Mitsuhiko Sugimoto.
粘附蛋白von Willebrand因子（VWF）在止血中起重要作用（1-3）。然而，过度的VWF功能可引发血栓性并发症。为了防止这种情况，VWF切割蛋白酶ADAMTS 1 - 3通过减少VWF多聚体的大小来负调节VWF功能，从而降低其血栓形成潜力（1-3）。由于VWF功能依赖于剪切应力（1-4），因此ADAMTS 13的相关性在微循环中可能更明显（5），其特征在于血流产生的高剪切应力。事实上，ADAMTS 13的功能缺陷会导致微血管（如动脉毛细血管）的血栓性闭塞，从而导致血栓性血小板减少性紫癜（3，6）。以前，我们（7）和其他人（8，9）报道，ADAMTS 13缺陷加重了大脑中动脉闭塞缺血/再灌注损伤小鼠模型中脑缺血性卒中的程度，表明ADAMTS 13具有神经保护作用。这些研究表明，ADAMTS 13在微循环中起着有益的作用，微循环对于保护器官功能至关重要，这提高了ADAMTS 13也可能在心肌梗死等冠状动脉缺血事件中发挥作用的可能性。我们在ADAMTS 13基因缺失（Adamts 13-/-）小鼠的急性心肌梗死实验模型中研究了这种可能性。如所述（7，10），我们的研究组在C57 BL/6背景下产生了Adamts 13-/-（KO）小鼠。所有小鼠均为12-14周龄，健康，可生育，体重为25-30克。根据奈良医科大学动物实验伦理审查委员会批准的方案进行小鼠实验。研究人员对每只动物的基因型不知情，直到所有研究完成。如前所述诱导小鼠实验性急性心肌梗死（AMI）（11）。简言之，在通过乙醚吸入麻醉并将聚乙烯管插入气管后，在开胸术下用呼吸机辅助呼吸，在距左心耳尖端2 mm处用聚酰胺缝线结扎冠状动脉左前降支。在假手术中进行相同的手术，但不结扎冠状动脉。在一些实验中，在手术后30分钟（min）内静脉内注射重组人ADAMTS 13（3 μg/小鼠，相当于2，800 U/kg）。所用的这种重组蛋白（命名为MDTCS）先前已描述（12）。简而言之，MDTCS从金属蛋白酶（M）结构域跨越到间隔区（S）结构域（氨基酸残基75-685）;它具有与整个ADAMTS 13分子相当的VWF切割活性，
The adhesive protein von Willebrand factor (VWF) plays an essential role on haemostasis (1–3). However, excessive functions of VWF could trigger thrombotic complications. To prevent this, the VWF-cleaving protease ADAMTS13 negatively regulates VWF function by reducing the size of VWF multimers, thereby decreasing their thrombogenic potential (1–3). Since the VWF function is dependent on shear stress (1–4), the relevance of ADAMTS13 may be more pronounced in the microcirculation (5), which is characterised by high shear stress created by blood flow. Indeed, functional deficiencies of ADAMTS13 cause thrombotic occlusion of the microvasculature, eg arterial capillaries, resulting in thrombotic thrombocytopenic purpura (3, 6). Previously, we (7) and others (8, 9) reported that ADAMTS13 deficiency aggravates the extent of brain ischaemic stroke in a mouse model of ischaemia/reperfusion injury by middle cerebral arterial occlusion, suggesting that ADAMTS13 is neuroprotective. These studies demonstrated that ADAMTS13 plays a beneficial role in the microcirculation, which is critical for the preservation of organ functions, raising the possibility that ADAMTS13 might also play a role in coronary ischaemic events such as myocardial infarction. We investigated this possibility in an experimental model of acute myocardial infarction in ADAMTS13 gene deleted (Adamts13-/-) mice.Adamts13-/-(KO) mice were generated on C57BL/6 background by our study group, as described (7, 10). All mice were 12–14 weeks of age, healthy, fertile, and had body weights of 25–30 grams. Mouse experiments were done according to protocols approved by the Ethics Review Committee for Animal Experimentation of Nara Medical University. Researchers were blinded to the genotype of each animal until all studies were completed. Experimental acute myocardial infarction (AMI) in mice was induced as previously described (11). Briefly, following anesthesia by diethyl ether inhalation and insertion of a polyethylene tube into trachea, the left anterior descending coronary artery was ligated with a polyamide suture 2 mm from the tip of the left auricle, under thoracotomy with ventilator-assisted respiration. The same procedure without coronary artery ligation was performed in sham operations. In some experiments, recombinant human ADAMTS13 (3 μg/mouse, equivalent to 2,800 U/kg) was injected intravenously in 30 minutes (min) after the operation. This recombinant protein (designated as MDTCS) used was previously described (12). In brief, MDTCS spans from the metalloproteinase (M) domain to spacer (S) domain (amino acid residues 75–685); it possesses VWF-cleaving activity equivalent to whole ADAMTS13 molecule,