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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H2S biosynthesis and catabolism: new insights from molecular studies.
TL;DR: Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H2S within tissues, revealing new insights into the biology of H20 within the cardiovascular system, inflammatory disease, and in cell signalling.
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H2S-Induced Sulfhydration: Biological Function and Detection Methodology.
TL;DR: This review summarizes recent studies of hydrogen sulfide-induced sulfhydration as a posttranslational modification, an important biological function of hydrogen sulphide, and sulfhydrated proteins are introduced and discusses the main methods of detecting sulfHydration of proteins.
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Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology
TL;DR: The biochemistry, metabolism, and signaling function of hydrogen sulfide, as well as its interplay with the other gasotransmitters, NO and CO, are reviewed.
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Cystathionine-β-Synthase: Molecular Regulation and Pharmacological Inhibition.
TL;DR: Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used “CBS inhibitors” and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.
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Evolution of Hydrogen Sulfide Therapeutics to Treat Cardiovascular Disease.
TL;DR: Recently developed H2S therapeutics are discussed, signaling pathways that are influenced by H2s-dependent sulfhydration are introduced, and the dual-protective effect of H 2S in cardiorenal syndrome is explored.
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H2S Signals Through Protein S-Sulfhydration
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