Cathepsin K Deficiency Impaired Ischemia-Induced Neovascularization in Aged Mice

Abstract

Background. Aging is a major risk factor for cardiovascular disease. Cysteine protease cathepsin K (CatK) has been implicated in the process of angiogenesis, but the exact roles of individual CatK in vessel formation during aging are poorly understood. Methods and Results. To study the putative role of CatK in ischemia-induced angiogenesis, we applied a hindlimb ischemia model to aged wild-type (CatK+/+) and CatK-deficient (CatK−/−) mice. A serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in the aged CatK−/−mice was impaired throughout the follow-up period. On postoperative day 14, CatK deficiency had also impaired capillary formation. CatK deficiency reduced the levels of cleaved Notch1, phospho-Akt, and/or vascular endothelial growth factor (VEGF) proteins in the ischemic muscles and bone marrow-derived c-Kit+ cells. A flow cytometry analysis revealed that CatK deficiency reduced the numbers of endothelial progenitor cell (EPC)-like CD31+/c-Kit+ cells in the peripheral blood as well as the ischemic vasculature. In vitro experiments, CatK−/− impaired bone-derived c-Kit+ cellular functions (migration, invasion, proliferation, and tubulogenesis) in aged mice. Our findings demonstrated that aging impaired the ischemia-induced angiogenesis associated with the reductions of the production and mobilization of CD31+/c-Kit+ cells in mice. Conclusions. These findings established that the impairment of ischemia-induced neovascularization in aged CatK−/− mice is due, at least in part, to the reduction of EPC mobilization and the homing of the cells into vasculature that is associated with the impairment of Notch1 signaling activation at advanced ages.

Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway

“…CTSK is involved in ECM remodeling [ 41 , 92 ], and our results from balicatib-mediated blockage of CTSK activity resulted in increased ECM proteins. To understand the role of CTSK in ECM remodeling, we studied the effects of AdCTSK on the distribution and levels of ECM proteins.…”

Young bone marrow transplantation prevents aging‐related muscle atrophy in a senescence‐accelerated mouse prone 10 model

“…Aging has been shown to cause a harmful change in BM‐derived stem cell functions. 15 , 17 , 33 As shown in Figure 5A and 5B , the numbers of TUNEL + cells were lower in the BM‐derived integrin‐α + cells of YBMT mice compared with the non‐YBMT mice. We observed that the numbers of Pax7 + cells were higher in the both muscles of the YBMT mice compared with the control mice ( Figure 5C ).…”

“…The use of double immunofluorescence revealed that compared with the muscles of control mice, the soleus and gastrocnemius muscles of the YBMT mice exhibited a diffuse and strong positive staining signal for desmin ( Figure 4A), suggesting that BM‐MSCs might contribute to skeletal muscle regeneration. Aging has been shown to cause a harmful change in BM‐derived stem cell functions 15,17,33 . As shown in Figure 5A and 5B, the numbers of TUNEL + cells were lower in the BM‐derived integrin‐α + cells of YBMT mice compared with the non‐YBMT mice.…”

The many roles of cathepsins in restenosis

“…Recent multicenter studies have demonstrated that by degrading the extracellular matrix and interacting with VEGF, Cats play important roles in angiogenesis [ [36] , [37] , [38] , [39] , [40] ]. In one study, it was discovered that CatK gene knockout could impair the regeneration of blood vessels in old mice; another report showed that CatL levels and tumor blood vessel regeneration are directly and closely related [ 36 , 37 ]. Together, these studies indicate that Cats might contribute to the process of blood vessel regeneration, although the specific mechanism remains uncertain.…”