Xiang Li1, Xian Wu Cheng2, Lina Hu3, Hongxian Wu4, Chang-Ning Hao4, Haiying Jiang5, Enbo Zhu1, Zhe Huang6, Aiko Inoue3, Takeshi Sasaki7, Qiuna Du8, Kyosuke Takeshita4, Kenji Okumura4, Toyoaki Murohara4, Masafumi Kuzuya3. 1. Department of Cardiology, Yanbian University Hospital, China. 2. 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. 3. Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan. 4. Department of Cardiology, Nagoya University Graduate School of Medicine, Japan. 5. Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan; Department of Physiology, Yanbian University School of Medicine, China. 6. Department of Neurology, Nagoya University Graduate School of Medicine, Japan. 7. Department of Anatomy, Hamamatsu University School of Medicine, Japan. 8. Department of Nephrology, Nagoya University Graduate School of Medicine, Japan.
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. METHODS AND 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.
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. METHODS AND 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: Svenja Memmert; Marjan Nokhbehsaim; Anna Damanaki; Andressa V B Nogueira; Alexandra K Papadopoulou; Christina Piperi; Efthimia K Basdra; Birgit Rath-Deschner; Werner Götz; Joni A Cirelli; Andreas Jäger; James Deschner Journal: BMC Oral Health Date: 2018-04-05 Impact factor: 2.757