title: Trivalent chromium inhibits TSP-1 expression, proliferation, and O-GlcNAc signaling in vascular smooth muscle cells in response to high glucose in vitro.
abstract: Trivalent chromium (Cr(3+)) is a mineral nutrient reported to have beneficial effects in glycemic and cardiovascular health. In vitro and in vivo studies suggest that Cr(3+) supplementation reduces the atherogenic potential and lowers the risk of vascular inflammation in diabetes. However, effects of Cr(3+) in vascular cells under conditions of hyperglycemia, characteristic of diabetes, remain unknown. In the present study we show that a therapeutically relevant concentration of Cr(3+) (100 nM) significantly downregulates a potent proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in human aortic smooth muscle cells (HASMC) stimulated with high glucose in vitro. Promoter-reporter assays reveal that this downregulation of TSP-1 expression by Cr(3+) occurs at the level of transcription. The inhibitory effects of Cr(3+) on TSP-1 were accompanied by significant reductions in O-glycosylation of cytoplasmic and nuclear proteins. Using Western blotting and immunofluorescence studies, we demonstrate that reduced protein O-glycosylation by Cr(3+) is mediated via inhibition of glutamine: fructose 6-phosphate amidotransferase, a rate-limiting enzyme of the hexosamine pathway, and O-linked N-acetylglucosamine (O-GlcNAc) transferase, a distal enzyme in the pathway that controls intracellular protein O-glycosylation. Additionally, we found that Cr(3+) attenuates reactive oxygen species formation in glucose-stimulated HASMC, suggesting an antioxidant effect. Finally, we report an antiproliferative effect of Cr(3+) that is specific for high glucose and conditions triggering elevated protein O-glycosylation. Taken together, these findings provide the first cellular evidence for a novel role of Cr(3+) to modulate aberrant vascular smooth muscle cell function associated with hyperglycemia-induced vascular complications.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio; and School of Biomedical Sciences, Kent State University, Kent, Ohio.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Ganguly
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio; and School of Biomedical Sciences, Kent State University, Kent, Ohio.
authors.forename: Soumyadip
authors.initials: S
authors.lastname: Sahu
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio; and.
authors.forename: Ronaldo J
authors.initials: RJ
authors.lastname: Chavez
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio; and School of Biomedical Sciences, Kent State University, Kent, Ohio praman@neomed.edu.
authors.forename: Priya
authors.initials: P
authors.lastname: Raman
mesh_terms: D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D002857:Chromium / Q000494:pharmacology*; D005636:Fructosephosphates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000235:genetics; D006031:Glycosylation / Q000187:drug effects; D006595:Hexosamines / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D005636:Fructosephosphates; D006595:Hexosamines; D017382:Reactive Oxygen Species; D019700:Thrombospondin 1; D002857:Chromium; D005973:Glutamine; C062519:fructose 3-phosphate; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; D005947:Glucose
keywords: O-glycosylation; reactive oxygen species; thrombospondin-1; trivalent chromium; vascular smooth muscle cells