Trivalent chromium inhibits TSP-1 expression, proliferation, and O-GlcNAc signaling in vascular smooth muscle cells in response to high glucose in vitro

• Published in: American Journal of Physiology: Cell Physiology Vol. 308; no. 2; pp. C111 - C122
• Main Authors: Ganguly, Rituparna, Sahu, Soumyadip, Chavez, Ronaldo J, Raman, Priya
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.01.2015
• Subjects: Aorta - drug effects; Aorta - metabolism; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cells; Cells, Cultured; Chromium; Chromium - pharmacology; Fructosephosphates - metabolism; Gene expression; Glucose; Glucose - metabolism; Glutamine - genetics; Glycosylation; Glycosylation - drug effects; Hexosamines - metabolism; Humans; Hyperglycemia - metabolism; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscular system; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; N-Acetylglucosaminyltransferases - genetics; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - genetics; Reactive Oxygen Species - metabolism; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Thrombospondin 1 - antagonists & inhibitors; Thrombospondin 1 - genetics; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; O-glycosylation; trivalent chromium; thrombospondin-1; vascular smooth muscle cells; reactive oxygen species
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00256.2014

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.