title: Cathepsin S activity controls ischemia-induced neovascularization in mice.
abstract: BACKGROUND
  Evidence from human and animal studies has demonstrated elevated levels of the cysteine protease cathepsin S (CatS) in hypoxic atherosclerotic lesions. We hypothesized that silencing of CatS gene would suppress ischemia-induced angiogenic action.
  
  
  RESULTS
  Left femoral artery ligation-induced ischemia in mice showed the increased expression and activity of CatS in the ischemic muscle. The CatS-deficiency (CatS(-/-)) mice showed impaired functional recovery following hindlimb ischemia and reduced levels of peroxisome proliferator-activated receptor-γ (PPAR-γ), phospho-Akt (p-Akt), p-endothelial nitric oxide synthase, p-extracellular signal-regulated kinase1/2 (Erk1/2), p-p38 mitogen-activated protein kinase, and vascular endothelial growth factor (VEGF) proteins, as well as reduced levels of matrix metalloproteinase-9 and macrophage infiltration in the ischemic muscles. In vitro, CatS silencing reduced the levels of these targeted essential molecules for angiogenesis and vasculogenesis. Together, the results indicated that the effects of CatS knockdown led to defective endothelial cell invasion, proliferation, and tube formation. This notion was reinforced by the finding that CatS inhibition led to a decreased PPAR-γ level and VEGF/Erk1/2 signaling activation in response to ischemia. CatS(-/-) resulted in decreased circulating EPC-like CD31(+)/c-Kit(+) cells, accompanied by the reduction of the cellular levels of PPAR-γ, p-Akt, and VEGF induced by ischemic stress. Transplantation of bone-marrow-derived mononuclear cells from CatS(+/+) mice restored neovascularization in CatS(-/-) mice.
  
  
  CONCLUSIONS
  CatS activity controls ischemia-induced neovascularization partially via the modulation of PPAR-γ and VEGF/Akt signaling activation.
authors: Department of Cardiology, Yanbian University Hospital, China.
authors: Xiang
authors: X
authors: Li
authors: Department of Cardiology, Yanbian University Hospital, China; Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan. Electronic address: xianwu@med.nagoya-u.ac.jp.
authors: Xian Wu
authors: XW
authors: Cheng
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan.
authors: Lina
authors: L
authors: Hu
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Japan.
authors: Hongxian
authors: H
authors: Wu
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, USA.
authors: Guo-Ping
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Japan.
authors: Chang-Ning
authors: CN
authors: Hao
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan; Department of Physiology, Yanbian University School of Medicine, China.
authors: Haiying
authors: H
authors: Jiang
authors: Department of Cardiology, Yanbian University Hospital, China.
authors: Enbo
authors: E
authors: Zhu
authors: Department of Neurology, Nagoya University Graduate School of Medicine, Japan.
authors: Zhe
authors: Z
authors: Huang
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan.
authors: Aiko
authors: A
authors: Inoue
authors: Department of Anatomy, Hamamatsu University School of Medicine, Japan.
authors: Takeshi
authors: T
authors: Sasaki
authors: Department of Nephrology, Nagoya University Graduate School of Medicine, Japan.
authors: Qiuna
authors: Q
authors: Du
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Japan.
authors: Kyosuke
authors: K
authors: Takeshita
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Japan.
authors: Kenji
authors: K
authors: Okumura
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Japan.
authors: Toyoaki
authors: T
authors: Murohara
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan.
authors: Masafumi
authors: M
authors: Kuzuya
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D005263:Femoral Artery / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007150:Immunohistochemistry; D007511:Ischemia / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047492:Peroxisome Proliferator-Activated Receptors; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D002403:Cathepsins; C028217:cathepsin S; D020780:Matrix Metalloproteinase 9
keywords: Angiogenesis; Cathepsin S; Ischemia; Peroxisome proliferator-activated receptor-γ