Cathepsin S Activity Controls Ischemia-Induced Neovascularization In Mice And Increased Serum Cathepsin K In Patients With Coronary Artery Disease

Aims:Cathepsin S (CatS) modify and degrade intracellular and extracellular various angiogenic substances to contribute to the regulation of endothelial cell (ECs) biological activity. Until now, few studies provide evidence Cat (CatL and K) participating pathophysiological angiogenesis,but it is unclear whether CatS plays role in ischemia-induced neovascularization. This study aims to investigate whether CatS deficiency impairs neovascularization and explore the related molecular mechanism and to investigate whether CatS deficiency impairs neovascularization and explore the related molecular mechanism. This study provides a theoretical basis for a new treatment target of ischemicdisease of lower extremity.Method and materials:The study by using the preparation of lower limb ischemia model to observe the changes of protein expression and activity of ischemia hypoxia injury on CatS, to define its role in ischemic vascular regeneration. Then through the study of CatS knockout mice revealed CatS regulated the function of endothelial cell (ECs) and endothelial progenitor cells (EPCs) by angiogenesis related signal pathways. In vitro.the study revealed the role of CatS in Ischemia-Induced Neovascularization using gene silencing/transfection,immunohistochemistry /immunofluorescence staining, flow cytometry (FACS),bone marrow transplant-tation, Western blot (Western Blot), aortic ring test (AorticRing Asssay) and other detection methods.Results:1.CatS deficiency impaired angiogenic action in response to the ischemic injury.2.CatS deficiency reduced the levels of PPAR-y, p-Erkl/2, IRS-2, p-Akt, p-p38MAPK, p-eNOS, and VEGF proteins in the ischemic muscle tissues. 3.siCatS reduced cell invasion proliferation and tubugenic activity accompanied with the reduction in PPAR-y, p-Erkl/2, IRS-2, p-Akt, p-p38MAPK, p-eNOS, and VEGF proteins in cultured HUVECsAThe levels of the targeted angiogenesis-related molecule phosphorylation and protein expression were lower in MNCs of CatS-/-mice received ischemic surgery than that of control CatS+/+ mice.5.Administration bone marrow transplant from control CatS+/+mice, improved angiogenic action of CatS-/- mice(in response to hypoxia).6. CatS inhibitior decreased blood flow recover and capillary formation(in the ischemic muscles).7.CatS inhibitior suppressed aorta-ring-derived microvessel formation significant ly.8.CatS inhibitior also suppressed The levels of the targeted angiogenesis-related molecule phosphorylation and protein expression in the ischemic muscles.Conclusions:CatS regulate the function of endothelial cell (ECs) and endothelial progenitor cells (EPCs) by angiogenesis related signal pathways. CatS activity controls neovascularization partially via the regulation of endothelial cell (ECs) and endothelial progenitor cells (EPCs) function by vascular related protein and the modulation of PPAR-y and VEGF/Akt signaling activation in response to hypoxia. CatS thus represents a new therapeutic target for ischemic vascular disease.