title: The Responses of Hyperglycemic Dividing Mesangial Cells to Heparin Are Mediated by the Non-reducing Terminal Trisaccharide.
abstract: Our previous studies showed: (i) that growth-arrested G0/G1 rat mesangial cells stimulated to divide in hyperglycemic medium initiate intracellular hyaluronan synthesis that induces autophagy and the cyclin D3-induced formation of a monocyte-adhesive extracellular hyaluronan matrix after completing cell division; and (ii) that heparin inhibits the intracellular hyaluronan and autophagy responses, but after completing division, induces hyaluronan synthesis at the plasma membrane with the formation of a larger monocyte-adhesive hyaluronan matrix. This study shows: (i) that the non-terminal trisaccharide of heparin is sufficient to initiate the same responses as intact heparin, (ii) that a fully sulfated tetrasaccharide isolated from bacterial heparin lyase 1 digests of heparin that contains a Δ-2S-iduronate on the non-reducing end does not initiate the same responses as intact heparin, and (iii) that removal of the Δ-2S-iduronate to expose the fully sulfated trisaccharide (GlcNS(6S)-IdoUA(2S)-GlcNS(6S)) does initiate the same responses as intact heparin. These results provide evidence that mammalian heparanase digestion of heparin and heparan sulfate exposes a cryptic motif on the non-reducing termini that is recognized by a receptor on dividing cells.
authors.affiliation: From the Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195 and.
authors.forename: Christina P
authors.initials: CP
authors.lastname: Wang
authors.affiliation: From the Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195 and.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Hascall
authors.affiliation: the Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors.forename: Fuming
authors.initials: F
authors.lastname: Zhang
authors.affiliation: the Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.affiliation: From the Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195 and.
authors.forename: Amina
authors.initials: A
authors.lastname: Abbadi
authors.affiliation: From the Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195 and wanga@ccf.org.
authors.forename: Aimin
authors.initials: A
authors.lastname: Wang
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D014312:Trisaccharides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D014312:Trisaccharides; D006493:Heparin
keywords: diabetes; diabetic nephropathy; endoplasmic reticulum stress (ER stress); glucose metabolism; heparanase; heparin; hyaluronan; inflammation; monocyte adhesive hyaluronan matrix; trisaccharide