1] Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan [2] Department of Sport Medicine, Nagoya University Graduate School of Medicine, Nagoya 464-8601, Aichiken, Japan [3] Department of Physiology and Pathophysiology, Yanbian University School of Medicine, Jilin 133000, Yanji, China [4].
1] Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan [2] Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 4668550, Aichiken, Japan [3] Department of Cardiology, Yanbian University Hospital, Jilin 133000, Yanji, China [4] Department of Internal Medicine, Kyung Hee University Hospital, Seoul1 30-702, Korea [5].
Nat Commun. 2014 Jun 4;5:3838. doi: 10.1038/ncomms4838.
Cysteine proteases play important roles in pathobiology. Here we reveal that cathepsin K (CatK) has a role in ischaemia-induced neovascularization. Femoral artery ligation-induced ischaemia in mice increases CatK expression and activity, and CatK-deficient mice show impaired functional recovery following hindlimb ischaemia. CatK deficiency reduces the levels of cleaved Notch1 (c-Notch1), Hes1 Hey1, Hey2, vascular endothelial growth factor, Flt-1 and phospho-Akt proteins of the ischaemic muscles. In endothelial cells, silencing of CatK mimicked, whereas CatK overexpression enhanced, the levels of c-Notch1 and the expression of Notch downstream signalling molecules, suggesting CatK contributes to Notch1 processing and activates downstream signalling. Moreover, CatK knockdown leads to defective endothelial cell invasion, proliferation and tube formation, and CatK deficiency is associated with decreased circulating endothelial progenitor cells-like CD31(+)/c-Kit(+) cells in mice following hindlimb ischaemia. Transplantation of bone marrow-derived mononuclear cells from CatK(+/+) mice restores the impairment of neovascularization in CatK(-/-) mice. We conclude that CatK may be a potential therapeutic target for ischaemic disease.
半胱氨酸蛋白酶在病理生物学中发挥重要作用。在这里，我们揭示组织蛋白酶 K (CatK) 在缺血诱导的新血管生成中起作用。在小鼠中，股动脉结扎诱导的缺血增加 CatK 的表达和活性，而 CatK 缺陷小鼠在下肢缺血后表现出功能恢复受损。CatK 缺乏降低了缺血肌肉中裂解的 Notch1 (c-Notch1)、Hes1、Hey1、Hey2、血管内皮生长因子、Flt-1 和磷酸化 Akt 蛋白的水平。在内皮细胞中，沉默 CatK 模拟了，而 CatK 过表达增强了 c-Notch1 的水平和 Notch 下游信号分子的表达，表明 CatK 有助于 Notch1 加工并激活下游信号。此外，CatK 敲低导致内皮细胞侵袭、增殖和管状形成缺陷，并且 CatK 缺乏与缺血后小鼠循环内皮祖细胞样 CD31(+)/c-Kit(+)细胞减少有关。从 CatK(+/+)小鼠的骨髓来源单核细胞移植恢复了 CatK(-/-)小鼠的新血管生成损伤。我们得出结论，CatK 可能是缺血性疾病的潜在治疗靶点。
