Li Bo, Zhou Yue, Chen Jing, Wang Tingting, Li Zhijuan, Fu Yili, Bi Changlong, Zhai Aixia
B Li, Department of Endocrinolog, The Fourth Hospital of Harbin Medical University, Harbin , China.
Y Zhou, Department of Endocrinolog, The Fourth Hospital of Harbin Medical University, Harbin , China.
J Mol Endocrinol. 2020 Jul 1. doi: 10.1530/JME-19-0242.
Diabetic foot ulcer (DFU) is a chronic and non-healing complication of diabetes that leads to high hospital costs and, in extreme cases, to amputation. Recent studies have reported that long non-coding RNAs (lncRNAs) are linked to various diabetes-related symptoms. Thus, we aim to explore the role of lncRNA H19 in the wound healing process following DFU. Fibroblasts were isolated from the ulcer margin tissues of DFU patients, with the expression of lncRNA H19, connective tissue growth factor (CTGF) or serum response factor (SRF) altered by lentivirus infection. Next, rat models of DFU induced by high glucose and lipid diet were established, which was also infected with corresponding lentivirus. The interaction among lncRNA H19, SRF and CTGF was determined. Afterwards, cell proliferation and apoptosis, angiogenesis, ECM remodeling and wound healing in DFU tissues were evaluated to explore the effects of lncRNA H19/SRF/CTGF and MAPK signaling pathway on DFU. CTGF was poorly expressed in ulcer tissues from DFU rats and patients. CTGF overexpression was shown to activate the MAPK signaling pathway to promote cell proliferation, ECM remodeling, angiogenesis and wound healing while inhibiting cell apoptosis. LncRNA H19 was validated to elevate CTGF expression by recruiting SRF to the promoter region of CTGF, thus accelerating cell proliferation, ECM remodeling and wound healing while repressing cell apoptosis. Furthermore, MAPK signaling pathway activation is confirmed to be the underlying mechanism behind lncRNA H19/CTGF/SRF-induced results. Thus, lncRNA H19 accelerated wound healing in DFU through elevation of CTGF and activation of the MAPK signaling pathway.
糖尿病足溃疡（DFU）是糖尿病的一种慢性且不愈合的并发症，会导致高昂的住院费用，在极端情况下会导致截肢。最近的研究报告称，长链非编码RNA（lncRNAs）与各种糖尿病相关症状有关。因此，我们旨在探讨lncRNA H19在DFU后伤口愈合过程中的作用。从DFU患者的溃疡边缘组织中分离出成纤维细胞，通过慢病毒感染改变lncRNA H19、结缔组织生长因子（CTGF）或血清反应因子（SRF）的表达。接下来，建立由高糖高脂饮食诱导的DFU大鼠模型，并同样感染相应的慢病毒。确定lncRNA H19、SRF和CTGF之间的相互作用。之后，评估DFU组织中的细胞增殖和凋亡、血管生成、细胞外基质重塑和伤口愈合，以探讨lncRNA H19/SRF/CTGF和丝裂原活化蛋白激酶（MAPK）信号通路对DFU的影响。CTGF在DFU大鼠和患者的溃疡组织中表达较低。CTGF过表达可激活MAPK信号通路，促进细胞增殖、细胞外基质重塑、血管生成和伤口愈合，同时抑制细胞凋亡。lncRNA H19被证实通过将SRF募集到CTGF的启动子区域来提高CTGF表达，从而加速细胞增殖、细胞外基质重塑和伤口愈合，同时抑制细胞凋亡。此外，MAPK信号通路激活被确认为lncRNA H19/CTGF/SRF诱导结果背后的潜在机制。因此，lncRNA H19通过提高CTGF水平和激活MAPK信号通路加速了DFU的伤口愈合。
