期刊
ONCOTARGET
卷 8, 期 42, 页码 72584-72596出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.19983
关键词
sphingomyelinase; ADAM17; apoptosis; TNF-alpha; TNFR1
资金
- Deutsche Forschungsgemeinschaft [CRC877, RTG1743]
- Cluster of Excellence 'Inflammation at Interfaces'
ADAM17, a prominent member of the Disintegrin and Metalloproteinase (ADAM) family, is an important regulator of endothelial cell proliferation and cell survival. The protease controls vital cellular functions through cleavage of growth factors, cytokines and their receptors including transforming growth factor-alpha (TGF-alpha), tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptor 1 (TNFR1). TNF-alpha is the major inducer of endothelial cell death in cardiovascular diseases. The latter are also characterized by elevated plasma and tissue levels of extracellular sphingomyelinase (SMase). Whether the SMase affects ADAM activity and thus endothelial cell function has not been addressed to date. Here, we analyzed the effect of SMase on ADAM17-mediated shedding in COS7 cells and in human umbilical vein endothelial cells (HUVECs). Exposure to SMase significantly increased ADAM17-mediated release of alkaline-phosphatase (AP)-tagged TGF-alpha in COS7 cells and shedding of endogenously expressed TNFR1 in HUVECs. We previously presented evidence that surface exposure of phosphatidylserine (PS) is pivotal for ADAM17 to exert sheddase function. We found that SMase treatment led to PS externalization in both cell types. Transient non-apoptotic PS exposure is often mediated by Ca2+-dependent phospholipid scramblases. Accordingly, the Ca2+-chelator EGTA markedly reduced the breakdown of phospholipid asymmetry and shedding of TGF-alpha and TNFR1. Moreover, sheddase activity was significantly diminished in the presence of the competing PS-headgroup OPLS. SMase-stimulated TNFR1 shedding strikingly diminished TNF-alpha-induced signalling cascades and endothelial cell death. Taken together, our data suggest that SMase activity might act as protective factor for endothelial cells in cardiovascular diseases.
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