Shear stress regulates cystathionine γ lyase expression to preserve endothelial redox balance and reduce membrane lipid peroxidation

  • Cystathionine γ lyase (CSE) is the major source of hydrogen sulfide-derived species (H2Sn) in endothelial cells and plays an important role in protecting against atherosclerosis. Here we investigated the molecular mechanisms underlying the regulation of CSE expression in endothelial cells by fluid shear stress/flow. Fluid shear stress decreased CSE expression in human and murine endothelial cells and was negatively correlated with the transcription factor Krüppel-like factor (KLF) 2. CSE was identified as a direct target of the KLF2-regulated microRNA, miR-27b and high expression of CSE in native human plaque-derived endothelial cells, was also inversely correlated with KLF2 and miR-27b levels. One consequence of decreased CSE expression was the loss of Prx6 sulfhydration (on Cys47), which resulted in Prx6 hyperoxidation, decamerization and inhibition, as well as a concomitant increase in endothelial cell reactive oxygen species and lipid membrane peroxidation. H2Sn supplementation in vitro was able to reverse the redox state of Prx6. Statin therapy, which is known to activate KLF2, also decreased CSE expression but increased CSE activity by preventing its phosphorylation on Ser377. As a result, the sulfhydration of Prx6 was partially restored in samples from plaque containing arteries from statin-treated donors. Taken together, the regulation of CSE expression by shear stress/disturbed flow is dependent on KLF2 and miR-27b. Moreover, in murine and human arteries CSE acts to maintain endothelial redox balance at least partly by targeting Prx6 to prevent its decamerization and inhibition of its peroxidase activity.
Metadaten
Author:Sofia Iris BibliORCiD, Jiong Hu, Matthias LeisegangORCiDGND, Janina Wittig, Sven ZukunftORCiD, Andrea Kapasakalidi, Beate Fißlthaler, Diamantis I. TsilimigrasORCiD, Georgios Zografos, Konstantinos FilisORCiD, Ralf BrandesORCiDGND, Andreas PapapetropoulosORCiD, Fragiska Sigala, Ingrid FlemingORCiD
URN:urn:nbn:de:hebis:30:3-518215
DOI:https://doi.org/10.1016/j.redox.2019.101379
ISSN:2213-2317
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/31759247
Parent Title (English):Redox Biology
Publisher:Elsevier
Place of publication:Amsterdam [u. a.]
Document Type:Article
Language:English
Year of Completion:2019
Date of first Publication:2019/11/13
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/11/27
Volume:28
Issue:Art. 101379
Page Number:10
First Page:1
Last Page:10
Note:
© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
HeBIS-PPN:45637762X
Institutes:Medizin / Medizin
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0