Ren-Jie Xiao: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China.
Tian-Jiao Wang: State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
Dan-Yin Wu: Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China.
Shui-Fa Yang: Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China.
Hai Gao: Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China.
Pei-Dong Gan: Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China.
Yang-Yan Yi: Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China.
You-Lai Zhang: Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China. youlaizhang@163.com.
BACKGROUND: diabetic wound injury is a significant and common complication in individuals with diabetes. N6-methyladenosine (m6A)-related epigenetic regulation is widely involved in the pathogenesis of diabetes complications. However, the function of m6A methyltransferase Wilms tumor 1-associated protein (WTAP) in diabetic wound healing remains elusive. AIM: To investigate the potential epigenetic regulatory mechanism of WTAP during diabetic wound healing. METHODS: Human umbilical vein endothelial cells (HUVECs) were induced with high glucose (HG) to establish cell model. Male BALB/c mice were intraperitoneally injected with streptozotocin to mimic diabetes, and full-thickness excision was made to mimic diabetic wound healing. HG-induced HUVECs and mouse models were treated with WTAP siRNAs and DNA methyltransferase 1 (DNMT1) overexpression vectors. Cell viability and migration ability were detected by cell counting kit-8 and Transwell assays. angiogenesis was measured using a tube formation experiment. The images of wounds were captured, and re-epithelialization and collagen deposition of skin tissues were analyzed using hematoxylin and eosin staining and Masson's trichrome staining. RESULTS: The expression of several m6A methyltransferases, including METTL3, METTL14, METTL16, KIAA1429, WTAP, and RBM15, were measured. WTAP exhibited the most significant elevation in HG-induced HUVECs compared with the normal control. WTAP depletion notably restored cell viability and enhanced tube formation ability and migration of HUVECs suppressed by HG. The unclosed wound area of mice was smaller in WTAP knockdown-treated mice than in control mice at nine days post-wounding, along with enhanced re-epithelialization rate and collagen deposition. The m6A levels on DNMT1 mRNA in HUVECs were repressed by WTAP knockdown in HUVECs. The mRNA levels and expression of DNMT1 were inhibited by WTAP depletion in HUVECs. Overexpression of DNMT1 in HUVECs notably reversed the effects of WTAP depletion on HG-induced HUVECs. CONCLUSION: WTAP expression is elevated in HG-induced HUVECs and epigenetically regulates the m6A modification of DNMT1 to impair diabetic wound healing.
