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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
Regulation and role of endogenously produced hydrogen sulfide in angiogenesis.
Antonia Katsouda,Sofia Iris Bibli,Anastasia Pyriochou,Csaba Szabó,Andreas Papapetropoulos,Andreas Papapetropoulos +5 more
TL;DR: Endogenously produced H2S up-regulates expression of the key angiogenic factor vascular endothelial growth factor and contributes to theAngiogenic signaling in response to VEGF.
Journal ArticleDOI
Beyond a Gasotransmitter: Hydrogen Sulfide and Polysulfide in Cardiovascular Health and Immune Response.
TL;DR: Evidence is emerging that many biological effects of H2S may indeed be due to polysulfide and persulfide activation of signaling pathways and reactivity with discrete small molecules, and how sulfide metabolites contribute to key chemical biology reactions involved in cardiovascular health and immune responses is still unclear.
Journal ArticleDOI
Protein S‐sulfhydration by hydrogen sulfide in cardiovascular system
TL;DR: The S‐sulfhydrated proteins may be potential novel targets for therapeutic intervention and drug design in the cardiovascular system, which may accelerate the development and application of H2S‐related drugs in the future.
Journal ArticleDOI
Hydrogen Sulfide in Pharmacotherapy, Beyond the Hydrogen Sulfide-Donors.
TL;DR: Data regarding sulfur drugs commonly used in clinical practice that can support the hypothesis about H2S-dependent pharmacotherapeutic effects of these drugs are reviewed.
Journal ArticleDOI
Hydrogen Sulfide and Vascular Regulation-An Update
Boyang Lv,Selena Chen,Chaoshu Tang,Chaoshu Tang,Hongfang Jin,Junbao Du,Junbao Du,Yaqian Huang +7 more
TL;DR: The role of hydrogen sulfide (H2S) in vascular physiology and pathophysiology has been investigated in animal and cell experiments and even in the clinical investigation as discussed by the authors, and the design and application of novel H2S donors have significant clinical implications in the treatment of vascular related diseases.
References
More filters
Journal ArticleDOI
Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.
Fouad Shalaby,Janet Rossant,Janet Rossant,Terry P. Yamaguchi,Terry P. Yamaguchi,Marina Gertsenstein,Xiang-Fu Wu,Xiang-Fu Wu,Martin L. Breitman,Martin L. Breitman,Andre C. Schuh +10 more
TL;DR: The generation of mice deficient in Flk-1 by disruption of the gene using homologous recombination in embryonic stem (ES) cells is reported, indicating that FlK-1 is essential for yolk-sac blood-island formation and vasculogenesis in the mouse embryo.
Journal ArticleDOI
VEGF receptor signalling - in control of vascular function.
TL;DR: Recent insights have shed light onto VEGFR signal transduction and the interplay between different V EGFRs and VEGF co-receptors in development, adult physiology and disease.
Journal Article
Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.
TL;DR: Since the enzymatic abnormalities in both disorders share certain metabolic consequences, the conclusion has been reached that an elevated concentration of homocysteine, homocystine, or a derivative of hornocysteines is the common factor leading to arterial damage.
Journal ArticleDOI
Homocysteine lowering and cardiovascular events after acute myocardial infarction.
Kaare H. Bønaa,Inger Njølstad,Per Magne Ueland,Henrik Schirmer,Aage Tverdal,Terje K. Steigen,Harald Wang,Jan Erik Nordrehaug,Egil Arnesen,Knut Rasmussen +9 more
TL;DR: Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction and a harmful effect from combined B vitamin treatment was suggested.
Journal ArticleDOI
H2S Signals Through Protein S-Sulfhydration
Asif K. Mustafa,Moataz M. Gadalla,Nilkantha Sen,Seyun Kim,Weitong Mu,Sadia K. Gazi,Roxanne K. Barrow,Guangdong Yang,Rui Wang,Solomon H. Snyder +9 more
TL;DR: Ex vivo endogenous H2S physiologically modifies cysteine residues in many proteins, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and actin, converting Cysteine -SH groups to -SSH groups in a process the authors call S-sulfhydration.