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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Osteopontin is proteolytically processed by matrix metalloproteinase 9
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Osteopontin is proteolytically processed by matrix metalloproteinase 9

机译：骨桥蛋白由基质金属蛋白酶9进行蛋白水解处理

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Osteopontin is robustly upregulated following myocardial infarction (MI), which suggests that it has an important role in post-MI remodeling of the left ventricle (LV). Osteopontin deletion results in increased LV dilation and worsened cardiac function. Thus, osteopontin exerts protective effects post-MI, but the mechanisms have yet to be defined. Matrix metalloproteinases (MMPs) regulate LV remodeling post-MI, and osteopontin is a known substrate for MMP-2, -3, -7, and -9, although the cleavage sites have not been mapped. Osteopontin-derived peptides can exert distinct biological functions that may depend on their cleavage sites. We mapped the MMP-9 cleavage sites via LC-MS/MS analysis using label-free and N-terminal labeling methods, and compared them with those of MMP-2, -3, and -7. Each MMP yielded a unique cleavage profile with few overlapping cleavage sites. Using synthetic peptides, we validated 3 sites for MMP-9 cleavage at amino acid positions 151-152, 193-194, and 195-196. Four peptides were synthesized based on the upstream-and downstream-generated fragments and were tested for biological activity in isolated cardiac fibroblasts. Two peptides increased cardiac fibroblast migration rates post-wounding (p < 0.05 compared with the negative control). Our study highlights the importance of osteopontin processing, and confirms that different cleavage sites generate osteopontin peptides with distinct biological functions.
机译：心肌梗塞（MI）后，骨桥蛋白强烈上调，这表明它在MI后左心室（LV）重塑中具有重要作用。骨桥蛋白的缺失导致左室扩张增加和心脏功能恶化。因此，骨桥蛋白在心肌梗死后发挥保护作用，但其机制尚待确定。基质金属蛋白酶（MMP）调节MI后的LV重塑，并且骨桥蛋白是MMP-2，-3，-7和-9的已知底物，尽管切割位点尚未定位。骨桥蛋白衍生的肽可以发挥不同的生物学功能，这可能取决于它们的切割位点。我们使用无标记和N端标记方法通过LC-MS / MS分析绘制了MMP-9切割位点，并与MMP-2，-3和-7进行了比较。每个MMP产生唯一的切割图谱，几乎没有重叠的切割位点。使用合成肽，我们验证了MMP-9切割在氨基酸位置151-152、193-194和195-196处的3个位点。基于上游和下游产生的片段合成了四种肽，并测试了分离的心脏成纤维细胞的生物学活性。两种肽在伤口后增加了心脏成纤维细胞的迁移速率（与阴性对照相比，p <0.05）。我们的研究突出了骨桥蛋白加工的重要性，并证实了不同的切割位点会产生具有独特生物学功能的骨桥蛋白肽。

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