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FASEB J. 2016 Jan;30(1):441-56. doi: 10.1096/fj.15-278648. Epub 2015 Sep 24.

Cystathionine β-synthase regulates endothelial function via protein S-sulfhydration.

Author information

1
*Peggy and Charles Stephenson Cancer Center, Department of Obstetrics and Gynecology, Department of Pathology, and Department of Cell Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA; and Developmental Vascular Biology Program and Zebrafish Drug Screening Core, Department of Obstetrics and Gynecology, The Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
2
*Peggy and Charles Stephenson Cancer Center, Department of Obstetrics and Gynecology, Department of Pathology, and Department of Cell Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA; and Developmental Vascular Biology Program and Zebrafish Drug Screening Core, Department of Obstetrics and Gynecology, The Medical College of Wisconsin, Milwaukee, Wisconsin, USA priyabrata-mukherjee@ouhsc.edu resham-bhattacharya@ouhsc.edu.

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.

KEYWORDS:

VEGFRs; angiogenesis; metabolism; signal transduction

PMID:
26405298
PMCID:
PMC4684530
DOI:
10.1096/fj.15-278648
[Indexed for MEDLINE]
Free PMC Article

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