title: Inhibiting post-translational core fucosylation prevents vascular calcification in the model of uremia.
abstract: Vascular calcification (VC) is an independent risk factor for cardiovascular disease and mortality in uremia. Post-translational core fucosylation is implicated in a number of pathological processes. First, we investigated the role of core fucosylation and key TGF-β1 pathway receptors in calcified arteries in vivo. To determine whether blocking core fucosylation effectively inhibited VC and TGF-β/Smad signaling pathway, we established an in vitro model of phosphate-induced calcification in rat vascular smooth muscle cells (VSMCs) to assess the role of core fucosylation in VC. Core fucose could be detected at markedly higher levels in calcified VSMCs than control cells. Fut8 (α-1,6 fucosyltransferase), the only enzyme responsible for core fucosylation in humans, was significantly upregulated by high phosphate. Exposed to high phosphate media and blocking core fucosylation in VSMCs by knocking down Fut8 using a siRNA markedly reduced calcium and phosphorus deposition and Cbfα1 expression (osteoblast-specific transcription factor), and increased α-Sma expression (smooth muscle cell marker). Fut8 siRNA significantly inhibited TGF-β/Smad2/3 signaling activation in VSMCs cultured in high phosphate media. In conclusion, this study provides evidence to suggest core fucosylation plays a major role in the process of VC and appropriate blockade of core fucosylation may represent a potential therapeutic strategy for treating VC in end-stage renal disease.
authors: Graduate School of Dalian Medical University, Dalian, China; Department of Nephrology, Liaoning Translational Medicine Center of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Xinyu
authors: X
authors: Wen
authors: Graduate School of Dalian Medical University, Dalian, China; Department of Nephrology, Liaoning Translational Medicine Center of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Anqi
authors: A
authors: Liu
authors: Department of Nephrology, Liaoning Translational Medicine Center of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Changqing
authors: C
authors: Yu
authors: Department of Nephrology, Liaoning Translational Medicine Center of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Lingyu
authors: L
authors: Wang
authors: Department of Nephrology, Liaoning Translational Medicine Center of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Mengying
authors: M
authors: Zhou
authors: Department of Nephrology, Liaoning Translational Medicine Center of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Nan
authors: N
authors: Wang
authors: Department of Nephrology, Liaoning Translational Medicine Center of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Ming
authors: M
authors: Fang
authors: Department of Nephrology, Liaoning Translational Medicine Center of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Weidong
authors: W
authors: Wang
authors: Department of Nephrology, Liaoning Translational Medicine Center of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China. Electronic address: hllin@dlmedu.edu.cn.
authors: Hongli
authors: H
authors: Lin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005643:Fucose / Q000378:metabolism*; D005647:Fucosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D010710:Phosphates / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017534:Radial Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014511:Uremia / Q000378:metabolism* / Q000473:pathology; D061205:Vascular Calcification / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D010710:Phosphates; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D005643:Fucose; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat
keywords: TGFβ-R; Vascular calcification; α-1,6-fucosyltransferase