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首页> 外文期刊>American Journal of Physiology >Trivalent chromium inhibits TSP-1 expression, proliferation, and O-GlcNAc signaling in vascular smooth muscle cells in response to high glucose in vitro
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Trivalent chromium inhibits TSP-1 expression, proliferation, and O-GlcNAc signaling in vascular smooth muscle cells in response to high glucose in vitro

机译：三价铬抑制血管平滑肌细胞中的TSP-1表达，增殖和O-GLCNAC信号传导，响应于体外高葡萄糖

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摘要

Trivalent chromium (Cr3+) is a mineral nutrient reported to have beneficial effects in glycemic and cardiovascular health. In vitro and in vivo studies suggest that Cr3+ supplementation reduces the atherogenic potential and lowers the risk of vascular inflammation in diabetes. However, effects of Cr3+ in vascular cells under conditions of hyperglycemia, characteristic of diabetes, remain unknown. In the present study we show that a therapeutically relevant concentration of Cr3+ (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 Cr3+ occurs at the level of transcription. The inhibitory effects of Cr3+ on TSP-1 were accompanied by significant reductions in O-glycosylation of cytoplasmic and nuclear proteins. Using Western blotting and immunofiuorescence studies, we demonstrate that reduced protein O-glycosylation by Cr3+ is mediated via inhibition of glutamine: fructose 6-phosphate amidotransferase, a rate-limiting enzyme of the hexosamine pathway, and O-linked 7V-acetylglucosamine (0-GlcNAc) transferase, a distal enzyme in the pathway that controls intracellular protein O-glycosylation. Additionally, we found that Cr3+ attenuates reactive oxygen species formation in glucose-stimulated HASMC, Suggesting an antioxidant effect. Finally, we report an antiprolifera-tive effect of Cr3+ that is specific for high glucose and conditions triggering elevated protein <9-glycosylation. Taken together, these findings provide the first cellular evidence for a novel role of Cr3+ to modulate aberrant vascular smooth muscle cell function associated with hyperglycemia-induced vascular complications.
机译：三价铬（Cr3 +）是据报道的矿物质营养素，在血糖和心血管健康方面具有有益效果。体外和体内研究表明，CR3 +补充降低了动脉粥样硬化潜力，降低了糖尿病血管炎症的风险。然而，在高血糖症条件下，血管细胞的Cr3 +在糖尿病的特征中的影响仍然未知。在本研究中，我们表明，治疗相关浓度的Cr3 +（100nm）的浓度显着下调了用高葡萄糖在体外刺激的人主动脉平滑肌细胞（HASMC）中的有效的嗜激菌性胰岛素蛋白血栓动素-1（TSP-1）。启动子报告者测定揭示CR3 +下调TSP-1表达的下调发生在转录水平。 CR3 +对TSP-1的抑制作用伴随着细胞质和核蛋白的O-糖基化的显着降低。使用蛋白质印迹和免疫致荧光研究，证明通过抑制谷氨酰胺的抑制来介导减少的蛋白质O-糖基化：果糖6-磷酸酰胺转移酶，六烷胺途径的速率限制酶，以及O与7V-乙酰葡糖胺（0- GLCNAC）转移酶，在控制细胞内蛋白O-糖基化的途径中的远端酶。此外，我们发现CR3 +衰减在葡萄糖刺激的HASMC中形成的反应性氧物种，表明抗氧化效果。最后，我们报告了Cr3 +的抗溶解作用，其特异于高葡萄糖和触发升高的蛋白质<9-糖基化的条件。总之，这些发现提供了CR3 +新颖作用的第一个细胞证据，以调节与高血糖诱导的血管并发症相关的异常血管平滑肌细胞功能。

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