OBJECTIVES: Friend leukemia integration 1 and erythroblast transformation-specific, important regulators of endothelial cell homeostasis, are reduced in microvascular endothelial cells in scleroderma patients, and their deficiency has been implicated in disease pathogenesis. The goal of this study was to identify the mechanisms involved in the protein turnover of friend leukemia integration 1 and erythroblast transformation-specific in microvascular endothelial cells. METHODS: The effects of lysosome and proteosome inhibitors on friend leukemia integration 1 and erythroblast transformation-specific levels were assessed by Western blotting and capillary morphogenesis. The effect of scleroderma and control sera on the levels of friend leukemia integration 1 and erythroblast transformation-specific was examined. RESULTS: The reduction in the protein levels of friend leukemia integration 1 and erythroblast transformation-specific in response to interferon α or Poly:(IC) was reversed by blocking either lysosomal (leupeptin and Cathepsin B inhibitor) or proteosomal degradation (MG132). MG132, leupeptin or CTSB-(i) also counteracted the anti-angiogenic effects of Poly:(IC) or interferon α. Scleroderma sera reduced protein levels of friend leukemia integration 1 and erythroblast transformation-specific in comparison to control sera. Treatment with CTSB(i) increased the levels of friend leukemia integration 1 and erythroblast transformation-specific in a majority of serum-treated samples. CONCLUSIONS: Inhibition of cathepsin B was effective in reversing the reduction of friend leukemia integration 1 and erythroblast transformation-specific protein levels after treatment with interferon α or scleroderma sera, suggesting that targeting cathepsin B may have a beneficial effect in SSc vascular disease.
OBJECTIVES:Friend leukemia integration 1 and erythroblast transformation-specific, important regulators of endothelial cell homeostasis, are reduced in microvascular endothelial cells in sclerodermapatients, and their deficiency has been implicated in disease pathogenesis. The goal of this study was to identify the mechanisms involved in the protein turnover of friend leukemia integration 1 and erythroblast transformation-specific in microvascular endothelial cells. METHODS: The effects of lysosome and proteosome inhibitors on friend leukemia integration 1 and erythroblast transformation-specific levels were assessed by Western blotting and capillary morphogenesis. The effect of scleroderma and control sera on the levels of friend leukemia integration 1 and erythroblast transformation-specific was examined. RESULTS: The reduction in the protein levels of friend leukemia integration 1 and erythroblast transformation-specific in response to interferon α or Poly:(IC) was reversed by blocking either lysosomal (leupeptin and Cathepsin B inhibitor) or proteosomal degradation (MG132). MG132, leupeptin or CTSB-(i) also counteracted the anti-angiogenic effects of Poly:(IC) or interferon α. Scleroderma sera reduced protein levels of friend leukemia integration 1 and erythroblast transformation-specific in comparison to control sera. Treatment with CTSB(i) increased the levels of friend leukemia integration 1 and erythroblast transformation-specific in a majority of serum-treated samples. CONCLUSIONS: Inhibition of cathepsin B was effective in reversing the reduction of friend leukemia integration 1 and erythroblast transformation-specific protein levels after treatment with interferon α or scleroderma sera, suggesting that targeting cathepsin B may have a beneficial effect in SSc vascular disease.
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