Targeting Cx43 and N-cadherin, which are abnormally upregulated in venous leg ulcers, influences migration, adhesion and activation of Rho GTPases.
Targeting Cx43 and N-cadherin, which are abnormally upregulated in venous leg ulcers, influences migration, adhesion and activation of Rho GTPases.
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DOI：
10.1371/journal.pone.0037374
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Becker DL
中科院分区：
文献类型：
--
作者：
Mendoza-Naranjo A;Cormie P;Serrano AE;Hu R;O'Neill S;Wang CM;Thrasivoulou C;Power KT;White A;Serena T;Phillips AR;Becker DL
腿部静脉溃疡很难治愈，并且目前尚无有效的治疗方法，因此存在重大的医疗需求。在人类腿部静脉溃疡的伤口边缘活检中，我们发现与完整皮肤相比，真皮 N-钙粘蛋白、Zonula Occlusionns-1 和间隙连接蛋白 Connexin43 (Cx43) 显着上调，与急性愈合伤口中 Cx43 表达下调形成鲜明对比。我们针对这些蛋白质在 3T3 成纤维细胞中的表达来评估它们在腿部静脉溃疡愈合中的作用。在划痕伤口愈合试验中，Cx43 和 N-钙粘蛋白（而不是 Zonula Occlusionns-1）的敲低加速了细胞迁移。减少 Cx43 会增加高尔基体重新定向，同时减少细胞粘附和增殖。此外，Connexin43 和 N-钙粘蛋白敲低对划伤后成纤维细胞骨架动力学产生深远影响。这些细胞表现出较长的片状足突起，缺乏在受伤对照细胞的前缘看到的 F-肌动蛋白带。 Förster 共振能量转移和下拉实验揭示，这种表型伴随着 Rac-1 和 RhoA GTPases 的增强激活。 Cx43 和 N-钙粘蛋白是促进腿部静脉溃疡愈合的潜在治疗靶点，至少部分通过细胞粘附、迁移、增殖和细胞骨架动力学的独特贡献发挥作用。
Venous leg ulcers can be very hard to heal and represent a significant medical need with no effective therapeutic treatment currently available. In wound edge biopsies from human venous leg ulcers we found a striking upregulation of dermal N-cadherin, Zonula Occludens-1 and the gap junction protein Connexin43 (Cx43) compared to intact skin, and in stark contrast to the down-regulation of Cx43 expression seen in acute, healing wounds. We targeted the expression of these proteins in 3T3 fibroblasts to evaluate their role in venous leg ulcers healing. Knockdown of Cx43 and N-cadherin, but not Zonula Occludens-1, accelerated cell migration in a scratch wound-healing assay. Reducing Cx43 increased Golgi reorientation, whilst decreasing cell adhesion and proliferation. Furthermore, Connexin43 and N-cadherin knockdown led to profound effects on fibroblast cytoskeletal dynamics after scratch-wounding. The cells exhibited longer lamelipodial protrusions lacking the F-actin belt seen at the leading edge in wounded control cells. This phenotype was accompanied by augmented activation of Rac-1 and RhoA GTPases, as revealed by Förster Resonance Energy Transfer and pull down experiments. Cx43 and N-cadherin are potential therapeutic targets in the promotion of healing of venous leg ulcers, by acting at least in part through distinct contributions of cell adhesion, migration, proliferation and cytoskeletal dynamics.
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影响因子：
5.3
作者：
Itoh, RE;Kurokawa, K;Matsuda, M
通讯作者：
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影响因子：
20.3
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DOI：
10.1016/j.bjps.2004.12.022
发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
21.3
作者：
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