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Cystathionine β‐synthase regulates endothelial function via protein S ‐sulfhydration
Author(s) -
Saha Sounik,
Chakraborty Prabir K.,
Xiong Xunhao,
Dwivedi Shailendra Kumar Dhar,
Mustafi Soumyajit Banerjee,
Leigh Noah R.,
Ramchandran Ramani,
Mukherjee Priyabrata,
Bhattacharya Resham
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-278648
Subject(s) - cystathionine beta synthase , homocysteine , transcription factor , gene silencing , receptor , enos , glutathione , chemistry , hyperhomocysteinemia , microbiology and biotechnology , biology , biochemistry , medicine , enzyme , nitric oxide synthase , cysteine , gene
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 (H 2 S) 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 (Spl), which is a sulfhydration target of H 2 S at residues Cys68 and Cys755. Reinstating H 2 S 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. FASEB J. 30, 441‐456 (2016). www.fasebj.org