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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Involvement of HAND1 and CBS in maintenance of cardiac micro-architecture following obesity-induced heart failure
TL;DR: Results reveal that in high fat diet-induced cardiac stress, the over-expressions of HAND1 and CBS at the initial stages induce extensive alterations in cardiac architecture.
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Does risk of hyperhomocysteinemia depend on thiol-disulfide exchange reactions of albumin and homocysteine?
Lucia Coppo,Simona Scheggi,Graziella DeMontis,Raffaella Priora,Simona Frosali,Antonios Margaritis,Domenico Summa,Danila DiGiuseppe,Monica Ulivelli,Paolo Cherubini DiSimplicio +9 more
TL;DR: In this paper , the authors suggest that homocysteinylated albumin could be a new pathological factor, and that studies on the redox role of albumin and mixed disulfide production via thiol-disulfide exchange reactions could offer new therapeutic insights for reducing Hcy toxicity.
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