Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

Haiying Jiang, Xian Wu Cheng (), Guo-Ping Shi, Lina Hu, Aiko Inoue, Yumiko Yamamura, Hongxian Wu, Kyosuke Takeshita, Xiang Li, Zhe Huang, Haizhen Song, Masashi Asai, Chang-Ning Hao, Kazumasa Unno, Teruhiro Koike, Yoshiharu Oshida, Kenji Okumura, Toyoaki Murohara and Masafumi Kuzuya
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Haiying Jiang: Nagoya University Graduate School of Medicine
Xian Wu Cheng: Nagoya University Graduate School of Medicine
Guo-Ping Shi: Brigham and Women's Hospital and Harvard Medical School
Lina Hu: Nagoya University Graduate School of Medicine
Aiko Inoue: Nagoya University Graduate School of Medicine
Yumiko Yamamura: Nagoya University Graduate School of Medicine
Hongxian Wu: Nagoya University Graduate School of Medicine
Kyosuke Takeshita: Nagoya University Graduate School of Medicine
Xiang Li: Nagoya University Graduate School of Medicine
Zhe Huang: Nagoya University Graduate School of Medicine
Haizhen Song: Nagoya University Graduate School of Medicine
Masashi Asai: Graduate School of Biomedical Sciences, Nagasaki University
Chang-Ning Hao: Nagoya University Graduate School of Medicine
Kazumasa Unno: Nagoya University Graduate School of Medicine
Teruhiro Koike: Nagoya University Graduate School of Medicine
Yoshiharu Oshida: Nagoya University Graduate School of Medicine
Kenji Okumura: Nagoya University Graduate School of Medicine
Toyoaki Murohara: Nagoya University Graduate School of Medicine
Masafumi Kuzuya: Nagoya University Graduate School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4838

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