Τίτλος:
Shear stress regulates cystathionine γ lyase expression to preserve endothelial redox balance and reduce membrane lipid peroxidation: Regulation of CSE by KLF2 and miR-27b
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2019 The Authors
Συγγραφείς:
Bibli, S.-I.
Hu, J.
Leisegang, M.S.
Wittig, J.
Zukunft, S.
Kapasakalidi, A.
Fisslthaler, B.
Tsilimigras, D.
Zografos, G.
Filis, K.
Brandes, R.P.
Papapetropoulos, A.
Sigala, F.
Fleming, I.
Λέξεις-κλειδιά:
cystathionine gamma lyase; hydroxymethylglutaryl coenzyme A reductase inhibitor; kruppel like factor 2; membrane lipid; microRNA; microRNA 27b; peroxidase; protein peroxidase 6; reactive oxygen metabolite; unclassified drug; cystathionine gamma lyase; hydrogen sulfide; KLF2 protein, human; kruppel like factor; microRNA; MIRN27 microRNA, human; peroxiredoxin 6; PRDX6 protein, human, animal cell; animal experiment; artery blood flow; Article; controlled study; endothelium cell; enzyme activation; enzyme activity; enzyme inhibition; enzyme metabolism; enzyme regulation; human; human cell; human tissue; in vitro study; lipid peroxidation; nonhuman; oxidation reduction state; priority journal; protein depletion; protein expression; protein phosphorylation; protein targeting; shear stress; animal; atherosclerotic plaque; endothelium cell; gene expression regulation; genetics; HEK293 cell line; mechanical stress; metabolism; mouse; oxidation reduction reaction; umbilical vein endothelial cell, Animals; Cystathionine gamma-Lyase; Endothelial Cells; Gene Expression Regulation; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen Sulfide; Kruppel-Like Transcription Factors; Lipid Peroxidation; Mice; MicroRNAs; Oxidation-Reduction; Peroxiredoxin VI; Plaque, Atherosclerotic; Stress, Mechanical
DOI:
10.1016/j.redox.2019.101379
