Cystathionine β-synthase regulates endothelial function via protein S-sulfhydration
Sounik Saha,Prabir K. Chakraborty,Xunhao Xiong,Shailendra Kumar Dhar Dwivedi,Soumyajit Banerjee Mustafi,Noah R. Leigh,Ramani Ramchandran,Priyabrata Mukherjee,Resham Bhattacharya +8 more
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TLDR
It is shown that the loss of CBS function in endothelial cells (ECs) leads to a significant down‐regulation of cellular hydrogen sulfide (H2S) by 50% and of glutathione (GSH) by 40%, highlighting the importance of CBS‐mediated protein S‐sulfhydration in maintaining vascular health and function.Abstract:
Deficiencies of the human cystathionine β-synthase (CBS) enzyme are characterized by a plethora of vascular disorders and hyperhomocysteinemia. However, several clinical trials demonstrated that despite reduction in homocysteine levels, disease outcome remained unaffected, thus the mechanism of endothelial dysfunction is poorly defined. Here, we show that the loss of CBS function in endothelial cells (ECs) leads to a significant down-regulation of cellular hydrogen sulfide (H2S) by 50% and of glutathione (GSH) by 40%. Silencing CBS in ECs compromised phenotypic and signaling responses to the VEGF that were potentiated by decreased transcription of VEGF receptor (VEGFR)-2 and neuropilin (NRP)-1, the primary receptors regulating endothelial function. Transcriptional down-regulation of VEGFR-2 and NRP-1 was mediated by a lack in stability of the transcription factor specificity protein 1 (Sp1), which is a sulfhydration target of H2S at residues Cys68 and Cys755. Reinstating H2S but not GSH in CBS-silenced ECs restored Sp1 levels and its binding to the VEGFR-2 promoter and VEGFR-2, NRP-1 expression, VEGF-dependent proliferation, and migration phenotypes. Thus, our study emphasizes the importance of CBS-mediated protein S-sulfhydration in maintaining vascular health and function.-Saha, S., Chakraborty, P. K., Xiong, X., Dwivedi, S. K. D., Mustafi, S. B., Leigh, N. R., Ramchandran, R., Mukherjee, P., Bhattacharya, R. Cystathionine β-synthase regulates endothelial function via protein S-sulfhydration.read more
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Book ChapterDOI
Chapter Five – Protein Sulfhydration
Bindu D. Paul,Solomon H. Snyder +1 more
TL;DR: The biotin switch assay, originally developed to detect nitrosylation, has been modified to detect sulfhydration and the methodologies used to detect this modification are discussed.
Journal ArticleDOI
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Ann Van Campenhout,Corey S. Moran,Adam Parr,Paula Clancy,Catherine M. Rush,Hieronim Jakubowski,Jonathan Golledge +6 more
TL;DR: The presence of homocysteine in atheroma and its ability to enhance osteogenic cell differentiation may partly explain the association of homocrysteine with atherosclerotic events.
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Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells
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TL;DR: It is suggested that VEGF increases ctgf/ccn2 mRNA stability through mitogen-activated protein kinase–mediated intracellular signaling cascade(s), which can be inhibited posttranscriptionally by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells.