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首页> 外文期刊>Cell biology international. >Overexpression of the gap junction protein Cx43 as found in diabetic foot ulcers can retard fibroblast migration
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Overexpression of the gap junction protein Cx43 as found in diabetic foot ulcers can retard fibroblast migration

机译：在糖尿病足溃疡中发现间隙连接蛋白Cx43的过表达可延迟成纤维细胞迁移

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Poor healing of DFUs (diabetic foot ulcers) is a major clinical problem that can be extremely debilitating and lead to lower limb amputation. In the normal acute wound, the Cx43 (connexin 43) gap junction protein is down-regulated at the wound edge as a precursor to cell migration and healing. In fibroblasts from the human chronic DFU wound edge there was a striking and significant 10-fold elevation of Cx43 protein, as well as a 6-fold increase in N-cadherin and a 2-fold increase in ZO-1 (zonular occludin-1), compared with unwounded skin. In streptozotocin diabetic rats, Cx43 was found to be upregulated in intact dermal fibroblasts in direct proportion to blood glucose levels and increased 2-fold further in response to wounding of the skin. To mimic diabetes, NIH 3T3 fibroblasts were cultured under different concentrations of glucose or mannitol and Cx43 protein intercellular communication and migration rates were determined. Cultures of fibroblasts in very high (40 mM) glucose conditions showed significantly elevated Cx43 protein levels, as shown by immunostaining and Western blotting, and significantly increasing gap junctional communication, as shown by dye transfer. In scratch woundhealing assays, increased levels of Cx43 from high glucose resulted in repressed filopodial extensions and significantly slower migration rates than in either standard conditions (5.5 mM glucose) or the osmotic control of mannitol. Conversely, when glucose-induced Cx43 up-regulation was prevented with Cx43shRNA (Cx43 short-hairpin RNA) transduction, the fibroblasts extended long filopodia and migrated significantly faster. Cx43 protein was up-regulated in fibroblasts in DFUs as well as after high glucose exposure in culture which correlated with inhibition of fibroblast migration and is likely to contribute to impaired wound healing.
机译：DFU（糖尿病性足溃疡）的愈合不良是一个主要的临床问题，可能会极大地使人衰弱并导致下肢截肢。在正常的急性伤口中，Cx43（连接蛋白43）间隙连接蛋白在伤口边缘被下调，作为细胞迁移和愈合的前兆。在人类慢性DFU伤口边缘的成纤维细胞中，Cx43蛋白显着升高10倍，N-钙黏着蛋白增加6倍，ZO-1增加2倍（小zon骨1 ），与未受伤的皮肤相比。在链脲佐菌素糖尿病大鼠中，发现完整真皮成纤维细胞中Cx43的上调与血糖水平成正比，并随着皮肤受伤而增加2倍。为了模拟糖尿病，在不同浓度的葡萄糖或甘露醇下培养NIH 3T3成纤维细胞，并测定Cx43蛋白的细胞间通讯和迁移速率。如免疫染色和蛋白质印迹所示，在非常高（40 mM）葡萄糖条件下的成纤维细胞培养物显示Cx43蛋白水平显着升高，而染料转移则表明间隙连接通讯显着增加。在从头开始的伤口愈合试验中，与标准条件（5.5 mM葡萄糖）或甘露醇的渗透控制相比，高葡萄糖引起的Cx43水平升高导致丝状二足伸展受到抑制，迁移速率明显降低。相反，当通过Cx43shRNA（Cx43短发夹RNA）转导阻止葡萄糖诱导的Cx43上调时，成纤维细胞延长了长丝状伪足，并且迁移速度明显加快。 Cx43蛋白在DFU中的成纤维细胞中以及在高葡萄糖暴露于培养物中后均上调，这与抑制成纤维细胞迁移有关，并且可能导致伤口愈合受损。

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