Cathepsin K activity controls injury-related vascular repair in mice.
Cathepsin K activity controls injury-related vascular repair in mice.
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DOI：
10.1161/hypertensionaha.113.02141
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发表时间：
2014-03
期刊：
影响因子：
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通讯作者：
Kuzuya M
中科院分区：
文献类型：
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作者：
Hu L;Cheng XW;Song H;Inoue A;Jiang H;Li X;Shi GP;Kozawa E;Okumura K;Kuzuya M
组织蛋白酶K （CatK）是最有效的哺乳动物胶原酶之一。我们之前已经证明了CatK在人和动物动脉粥样硬化病变中的表达增加。在这里，我们假设消融CatK可以减轻损伤性内膜增生。雄性野生型（CatK+/+）和CatK缺陷型（CatK−/−）小鼠在右侧颈总动脉分叉近端处进行结扎或结扎和聚乙烯袖套置换术的组合损伤，然后在特定时间点进行形态学和生化研究。在手术第28天，与CatK +/+小鼠相比，CatK−/−显著减少了单一和联合损伤动脉的新内膜形成和新血管形成。在早期时间点，CatK−/−降低了病变巨噬细胞含量和内侧平滑肌细胞的增殖，单核细胞趋化蛋白-1、toll样受体-2、toll样受体-4、趋化因子配体-12的mRNA水平，以及与基质金属蛋白酶-2/-9相关的明胶溶解活性。主动脉外植体实验显示，与CatK+/+小鼠相比，CatK−/−小鼠的平滑肌细胞运动受损。此外，CatK−/−小鼠的平滑肌细胞和巨噬细胞通过重建的基底膜屏障具有较低的侵袭能力。这种血管保护作用可以通过反式环氧琥珀酰-l -乙酰氨基-{4-胍基}丁烷（E64d）抑制Cat来模拟。这些结果表明，CatK可能通过减少toll样受体2/-4介导的炎症和平滑肌细胞增殖，在损伤反应中新内膜病变形成中发挥重要作用，这表明通过调节CatK活性来控制血管内治疗相关再狭窄是一种新的治疗策略。
Cathepsin K (CatK) is one of the most potent mammalian collagenases. We showed previously the increased expression of CatK in human and animal atherosclerotic lesions. Here, we hypothesized that ablation of CatK mitigates injury-induced neointimal hyperplasia. Male wild-type (CatK+/+) and CatK-deficient (CatK−/−) mice underwent ligation or a combination of ligation and polyethylene cuff-replacement injuries to the right common carotid artery just proximal to its bifurcation, and they were then processed for morphological and biochemical studies at specific time points. On operative day 28, CatK−/− significantly reduced neointimal formation and neovessel formation in both single- and combination-injured arteries compared with the Cat K+/+ mice. At early time points, CatK−/− reduced the lesion macrophage contents and medial smooth muscle cell proliferation, the mRNA levels of monocyte chemoattractant protein-1, toll-like receptor-2, toll-like receptor-4, chemokine ligand-12, and the gelatinolytic activity related to matrix metalloproteinase-2/-9. An aorta-explant assay revealed that smooth muscle cell movement was impaired in the CatK−/− mice compared with the CatK+/+ mice. In addition, the smooth muscle cells and macrophages from CatK−/− mice had less invasive ability through a reconstituted basement membrane barrier. This vasculoprotective effect was mimicked by Cat inhibition with trans-epoxysuccinyl-L-leucylamido-{4-guanidino} butane (E64d). These results demonstrate an essential role of CatK in neointimal lesion formation in response to injury, possibly via the reduction of toll-like receptor-2/-4–mediated inflammation and smooth muscle cell proliferation, suggesting a novel therapeutic strategy for the control of endovascular treatment–related restenosis by regulating CatK activity.