Inhibition of microRNA-139-5p Improves Fibroblasts Viability and Enhances Wound Repair in Diabetic Rats Through AP-1 (c-Fos/c-Jun).

IF 2.8 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM
Jiake Mo, Jiaqi Zhang, Xubiao Meng, Fang Wang, Weian Tang, Ying Liu, Lanfang Fu, Fang Liang, Zhaohui Mo
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引用次数: 0

Abstract

Introductions: Diabetic foot ulcers (DFU) are notoriously difficult to heal, however, its underlying molecular mechanisms are unknown. MicroRNA-139-5p participates in various biological processes, including cancer and vascular endothelial injury, while its role in diabetic wound healing has not been reported.

Methods: Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin and a 1.0 cm full-layer dorsal skin wound was made to establish a diabetic wound model. On days 1, 4, 7, and 10 after the wound was made, a solution containing microRNA-139-5p antagomir or control was injected along the dorsal edge of the wound. Wound healing was analyzed using Image J, histological analysis and molecular analysis. Skin tissues from 4 diabetic and 4 matched non-diabetic ulcer patients were obtained to detect microRNA-139-5p expression. In vitro, human skin fibroblasts were transfected with microRNA-139-5p inhibitors/mimics, the function of the fibroblasts was evaluated by CCK-8 assay and scratch assay, and AP-1 (c-Fos/c-Jun) was detected.

Results: Obviously elevated microRNA-139-5p expression was detected in the wound tissue of the rats with diabetes and patients with DFUs, and the microRNA-139-5p antagonist-treated diabetic wounds had faster healing rates. The pace of diabetic wound re-epithelialization and angiogenesis was accelerated, and the expression of AP-1 family members (c-Fos/c-Jun), and VEGF, PDGF was upregulated in the wound tissue of diabetic rats treated with topical microRNA-139-5p antagomir. In vitro, the expression of microRNA-139-5p was up-regulated in human skin fibroblasts induced by high glucose treatment, while the function of the cell proliferation and migration was promoted and the level of AP-1 (c-Fos/c-Jun) was increased after transfected with the microRNA-139-5p inhibitor, and vice versa. Our study further verified that microRNA-139-5p regulated the migration of human skin fibroblasts by modulating c-Fos.

Conclusion: Inhibiting microRNA-139-5p improves fibroblasts viability and promotes diabetic wound healing, suggesting that this may be a therapeutic strategy for diabetic foot ulcer.

抑制microRNA-139-5p可通过AP-1改善糖尿病大鼠成纤维细胞活力并促进伤口修复(c-Fos/c-Jun)
众所周知,糖尿病足溃疡(DFU)难以治愈,然而,其潜在的分子机制尚不清楚。MicroRNA-139-5p参与多种生物过程,包括癌症和血管内皮损伤,但其在糖尿病伤口愈合中的作用尚未报道。方法:给SD大鼠腹腔注射链脲佐菌素,在背侧皮肤创面上制造1.0 cm全层糖尿病创面模型。创面后第1、4、7、10天,沿创面背缘注射含有microRNA-139-5p或对照的溶液。采用图像J、组织学分析和分子分析分析创面愈合情况。取4例糖尿病和4例匹配的非糖尿病性溃疡患者皮肤组织检测microRNA-139-5p的表达。体外用microRNA-139-5p抑制剂/模拟物转染人皮肤成纤维细胞,采用CCK-8法和scratch法评价成纤维细胞的功能,检测AP-1 (c-Fos/c-Jun)水平。结果:糖尿病大鼠和DFUs患者创面组织中microRNA-139-5p表达明显升高,且microRNA-139-5p拮抗剂治疗的糖尿病创面愈合速度更快。外用microRNA-139-5p拮抗剂治疗后,糖尿病大鼠创面再上皮化和血管生成速度加快,AP-1家族成员(c-Fos/c-Jun)和VEGF、PDGF的表达上调。在体外实验中,高糖处理诱导的人皮肤成纤维细胞中,microRNA-139-5p表达上调,转染microRNA-139-5p抑制剂后,细胞增殖和迁移功能增强,AP-1 (c-Fos/c-Jun)水平升高,反之亦然。我们的研究进一步证实了microRNA-139-5p通过调节c-Fos调控人皮肤成纤维细胞的迁移。结论:抑制microRNA-139-5p可提高成纤维细胞活力,促进糖尿病创面愈合,提示这可能是糖尿病足溃疡的一种治疗策略。
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来源期刊
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Pharmacology, Toxicology and Pharmaceutics-Pharmacology
CiteScore
5.90
自引率
6.10%
发文量
431
审稿时长
16 weeks
期刊介绍: An international, peer-reviewed, open access, online journal. The journal is committed to the rapid publication of the latest laboratory and clinical findings in the fields of diabetes, metabolic syndrome and obesity research. Original research, review, case reports, hypothesis formation, expert opinion and commentaries are all considered for publication.
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