Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia
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Author
Jiang, Haiying
Wu Cheng, Xian
Shi, Guo-Ping
Hu, Lina
Inoue, Aiko
Yamamura, Yumiko
Wu, Hongxian
Takeshita, Kyosuke
Li, Xiang
Huang, Zhe
Song, Haizhen
Asai, Masashi
Hao, Chang-Ning
Unno, Kazumasa
Koike, Teruhiro
Oshida, Yoshiharu
Okumura, Kenji
Murohara, Toyoaki
Kuzuya, Masafumi
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https://doi.org/10.1038/ncomms4838Metadata
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Jiang, Haiying, Xian Wu Cheng, Guo-Ping Shi, Lina Hu, Aiko Inoue, Yumiko Yamamura, Hongxian Wu, et al. 2014. “Cathepsin K-Mediated Notch1 Activation Contributes to Neovascularization in Response to Hypoxia.” Nature Communications 5 (1): 3838. doi:10.1038/ncomms4838.Abstract
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.Terms of Use
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