| First Author | Xu W | Year | 2019 |
| Journal | Circ J | Volume | 83 |
| Issue | 12 | Pages | 2537-2546 |
| PubMed ID | 31645525 | Mgi Jnum | J:295859 |
| Mgi Id | MGI:6455230 | Doi | 10.1253/circj.CJ-19-0325 |
| Citation | Xu W, et al. (2019) Cathepsin S-Mediated Negative Regulation of Wnt5a/SC35 Activation Contributes to Ischemia-Induced Neovascularization in Aged Mice. Circ J 83(12):2537-2546 |
| abstractText | BACKGROUND: Given that cathepsin S (CatS) gained attention due to its enzymatic and non-enzymatic functions in signaling, the role of CatS in ischemia-induced angiogenesis of aged mice was explored.Methods and Results:To study the role of CatS in the decline in aging-related vascular regeneration capacity, a hindlimb ischemia model was applied to aged wild-type (CatS(+/+)) and CatS-deficient (CatS(-/-)) mice. CatS(-/-)mice exhibited impaired blood flow recovery and capillary formation and increased levels of p-insulin receptor substrate-1, Wnt5a, and SC35 proteins and decreased levels of phospho-endothelial nitric oxide synthase (p-eNOS), p-mTOR, p-Akt, p-ERK1/2, p-glycogen synthase kinase-3alpha/beta, and galatin-3 proteins, as well as decreased macrophage infiltration and matrix metalloproteinase-2/-9 activities in the ischemic muscles. In vitro, CatS knockdown altered the levels of these targeted essential molecules for angiogenesis. Together, the results suggested that CatS(-/-)leads to defective endothelial cell functions and that CatS(-/-)is associated with decreased circulating endothelial progenitor cell (EPC)-like CD31(+)/c-Kit(+)cells. This notion was reinforced by the study finding that pharmacological CatS inhibition led to a declined angiogenic capacity accompanied by increased Wnt5a and SC35 levels and decreased eNOS/Akt-ERK1/2 signaling in response to ischemia. CONCLUSIONS: These findings demonstrated that the impairment of ischemia-induced neovascularization in aged CatS(-/-)mice is due, at least in part, to the attenuation of endothelial cell/EPC functions and/or mobilization associated with Wnt5a/SC35 activation in advanced age. |
