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

• Published in: Nature communications Vol. 5; no. 1; p. 3838
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.06.2014; Nature Publishing Group
• Subjects: 631/443/592/16; 631/80/86; 64/60; 692/308; 692/699/75/593; 96/95; Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Capillaries - pathology; Cathepsin K - genetics; Cathepsin K - metabolism; Cell Cycle Proteins - metabolism; Femoral Artery - surgery; Hindlimb - blood supply; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia - pathology; Ischemia; Laser-Doppler Flowmetry; Ligation; Mice; Mice, Knockout; multidisciplinary; Muscle, Skeletal - blood supply; Muscle, Skeletal - pathology; Neovascularization, Physiologic - genetics; Neovascularization, Physiologic - physiology; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Notch1 - metabolism; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Transcription Factor HES-1; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-1 - metabolism
• ISSN: 2041-1723; 2041-1723
• 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. The cathepsin family of proteases cleaves intracellular as well as extracellular proteins. Here the authors implicate cathepsin K in ischaemia-induced neovascularization by showing that cathepsin K increases the levels of cleaved Notch1 and downstream Notch signalling in endothelial cells.