title: Cathepsin K-mediated Notch1 activation contributes to neovascularization in response to hypoxia.
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.
authors.affiliation: 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].
authors.forename: Haiying
authors.initials: H
authors.lastname: Jiang
authors.affiliation: 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].
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.affiliation: Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan.
authors.forename: Lina
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 4668550, Aichiken, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yamamura
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 4668550, Aichiken, Japan.
authors.forename: Hongxian
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 4668550, Aichiken, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.affiliation: 1] Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan [2] Department of Cardiology, Yanbian University Hospital, Jilin 133000, Yanji, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Huang
authors.affiliation: 1] Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan [2] Department of Dermatology, No.3 People Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Haizhen
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Molecular Medicinal Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Nagasaki-ken, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Asai
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 4668550, Aichiken, Japan.
authors.forename: Chang-Ning
authors.initials: CN
authors.lastname: Hao
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 4668550, Aichiken, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Unno
authors.affiliation: Department of Sport Medicine, Nagoya University Graduate School of Medicine, Nagoya 464-8601, Aichiken, Japan.
authors.forename: Teruhiro
authors.initials: T
authors.lastname: Koike
authors.affiliation: Department of Sport Medicine, Nagoya University Graduate School of Medicine, Nagoya 464-8601, Aichiken, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Oshida
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 4668550, Aichiken, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 4668550, Aichiken, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kuzuya
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002196:Capillaries / Q000473:pathology*; D056657:Cathepsin K / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D005263:Femoral Artery / Q000601:surgery; D006614:Hindlimb / Q000098:blood supply; D018398:Homeodomain Proteins / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007511:Ischemia; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072056:Transcription Factor HES-1; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056657:Cathepsin K; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D051881:Receptor, Notch1; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; C489734:Hes1 protein, mouse; C120420:Hey1 protein, mouse; C485778:Hey2 protein, mouse; C497762:Notch1 protein, mouse; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse; C534132:Ctsk protein, mouse