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Hydrogen Sulfide Inhibits High Glucose-Induced sFlt-1 Production via Decreasing ADAM17 Expression in 3T3-L1 Adipocytes

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      Abstract

      Hydrogen sulfide (H 2S) has recently been identified as an endogenous gaseous signaling molecule. The aim of the present study was to investigate the effect of H 2S on high glucose- (HG-) induced ADAM17 expression and sFlt-1 production in 3T3-L1 adipocytes. Firstly, we found that HG DMEM upregulated the expression of ADAM17 and production of sFlt-1 in 3T3-L1 adipocytes. Knocking down ADAM17 attenuated the effect of high glucose on sFlt-1 production in adipocytes. HG decreased the expression of CSE and 3-MST, as well as the endogenous H 2S production. Furthermore, knocking down CSE and 3-MST significantly increased ADAM17 expression and sFlt-1 production. The addition of exogenous H 2S through the administration of sodium hydrosulfide (NaHS) inhibited HG-induced upregulation of ADAM17 expression and sFlt-1 production. In conclusion, decreased expression of CSE and 3-MST and the subsequent decrease in H 2S production contribute to high glucose-induced sFlt-1 production via activating ADAM17 in adipocytes. Exogenous H 2S donor NaHS has a potential therapeutic value for diabetic vascular complications.

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      Most cited references 33

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      Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis.

      Endoglin is a transforming growth factor-beta coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined the role of sEndoglin in tumor angiogenesis and the mechanism by which the extracellular domain of endoglin is released from the membrane.In colorectal cancer specimens, we observed high endothelial endoglin protein expression, accompanied with slightly lower sEndoglin levels in the circulation, compared with healthy controls. In vitro analysis using endothelial sprouting assays revealed that sEndoglin reduced spontaneous and vascular endothelial growth factor-induced endothelial sprouting. Human umbilical vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14 short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease. Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase in sEndoglin levels. Endoglin shedding required a direct interaction between endoglin and membrane-localized MMP-14. Using cleavage site mutants, we determined that MMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain. Taken together, this study shows that MMP-14 mediates endoglin shedding, which may regulate the angiogenic potential of endothelial cells in the (colorectal) tumor microenvironment. (c)2010 AACR.
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        The role of ADAM-mediated shedding in vascular biology.

        Within the vasculature the disintegrins and metalloproteinases (ADAMs) 8, 9, 10, 12, 15, 17, 19, 28 and 33 are expressed on endothelial cells, smooth muscle cells and on leukocytes. As surface-expressed proteases they mediate cleavage of vascular surface molecules at an extracellular site close to the membrane. This process is termed shedding and leads to the release of a soluble substrate ectodomain thereby critically modulating the biological function of the substrate. In the vasculature several surface molecules undergo ADAM-mediated shedding including tumour necrosis factor (TNF) α, interleukin (IL) 6 receptor α, L-selectin, vascular endothelial (VE)-cadherin, the transmembrane CX3C-chemokine ligand (CX3CL) 1, Notch, transforming growth factor (TGF) and heparin-binding epidermal growth factor (HB-EGF). These substrates play distinct roles in vascular biology by promoting inflammation, permeability changes, leukocyte recruitment, resolution of inflammation, regeneration and/or neovascularisation. Especially ADAM17 and ADAM10 are capable of cleaving many substrates with diverse function within the vasculature, whereas other ADAMs have a more restricted substrate range. Therefore, targeting ADAM17 or ADAM10 by pharmacologic inhibition or gene knockout not only attenuates the inflammatory response in animal models but also affects tissue regeneration and neovascularisation. Recent discoveries indicate that other ADAMs (e.g. ADAM8 and 9) also play important roles in vascular biology but appear to have more selective effects on vascular responses (e.g. on neovascularisation only). Although, targeting of ADAM17 and ADAM10 in inflammatory diseases is still a promising approach, temporal and spatial as well as substrate-specific inhibition approaches are required to minimise undesired side effects on vascular cells. Copyright © 2011 Elsevier GmbH. All rights reserved.
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          Hydrogen sulfide: a gasotransmitter of clinical relevance.

          Though the existence of hydrogen sulfide (H2S) in biological tissues has been known for over 300 years, it is the most recently appreciated of the gasotransmitters as a physiologic messenger molecule. The enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) had long been speculated to generate H2S, and inhibitors of these enzymes had been employed to characterize influences of H2S in various organs. Definitive evidence that H2S is a physiologic regulator came with the development of mice with targeted deletion of CSE and CBS. Best characterized is the role of H2S, formed by CSE, as an endothelial derived relaxing factor that normally regulates blood pressure by acting through ATP-sensitive potassium channels. H2S participates in various phases of the inflammatory process, predominantly exerting anti-inflammatory actions. Currently, the most advanced efforts to develop therapeutic agents involve the combination of H2S donors with non-steroidal anti-inflammatory drugs (NSAIDs). The H2S releasing moiety provides cytoprotection to gastric mucosa normally adversely affected by NSAIDs while the combination of H2S and inhibition of prostaglandin synthesis may afford synergistic anti-inflammatory influences.
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            Author and article information

            Affiliations
            1Department of Endocrinology, Chinese PLA 117th Hospital, Hangzhou 310013, China
            2Department of Physiology, Second Military Medical University, Shanghai 200433, China
            3Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
            Author notes

            Academic Editor: Qian Li

            Journal
            Int J Endocrinol
            Int J Endocrinol
            IJE
            International Journal of Endocrinology
            Hindawi
            1687-8337
            1687-8345
            2017
            27 June 2017
            : 2017
            5504937
            10.1155/2017/9501792
            Copyright © 2017 Tian-xiao Hu et al.

            This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

            Funding
            Funded by: Health Science and Technology Plan of Hangzhou
            Award ID: 2016B56
            Funded by: Medical Science and Technology Innovation Subject of Nanjing Region
            Award ID: 14ZX30
            Categories
            Research Article

            Endocrinology & Diabetes

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