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Cystathionine β-synthase regulates endothelial function via protein S-sulfhydration. FASEB J 2016 Jan;30(1):441-56

Date

09/26/2015

Pubmed ID

26405298

Pubmed Central ID

PMC4684530

DOI

10.1096/fj.15-278648

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.

Author List

Saha S, Chakraborty PK, Xiong X, Dwivedi SK, Mustafi SB, Leigh NR, Ramchandran R, Mukherjee P, Bhattacharya R

Author

Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Movement
Cell Proliferation
Cystathionine beta-Synthase
Endothelium, Vascular
Glutathione
Human Umbilical Vein Endothelial Cells
Humans
Hydrogen Sulfide
Neuropilins
Second Messenger Systems
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d