title: High-glucose inhibits human fibroblast cell migration in wound healing via repression of bFGF-regulating JNK phosphorylation.
abstract: One of the major symptoms of diabetes mellitus (DM) is delayed wound healing, which affects large populations of patients worldwide. However, the underlying mechanism behind this illness remains elusive. Skin wound healing requires a series of coordinated processes, including fibroblast cell proliferation and migration. Here, we simulate DM by application of high glucose (HG) in human foreskin primary fibroblast cells to analyze the molecular mechanism of DM effects on wound healing. The results indicate that HG, at a concentration of 30 mM, delay cell migration, but not cell proliferation. bFGF is known to promote cell migration that partially rescues HG effects on cell migration. Molecular and cell biology studies demonstrated that HG enhanced ROS production and repressed JNK phosphorylation, but did not affect Rac1 activity. JNK and Rac1 activation were known to be important for bFGF regulated cell migration. To further confirm DM effects on skin repair, a type 1 diabetic rat model was established, and we observed the efficacy of bFGF on both normal and diabetic rat skin repair. Furthermore, proteomic studies identified an increase of Annexin A2 protein nitration in HG-stressed fibroblasts and the nitration was protected by activation of bFGF signaling. Treatment with FGFR1 and JNK inhibitors delayed cell migration and increased Annexin A2 nitration levels, indicating that Annexin A2 nitration is modulated by bFGF signaling via activation of JNK. Together with these results, our data suggests that the HG-mediated delay of cell migration is linked to the inhibition of bFGF signaling, specifically through JNK suppression.
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China.
authors.forename: Yuan Hu
authors.initials: YH
authors.lastname: Xuan
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China; The Third Affiliated Hospital of the Wenzhou Medical University, Wenzhou, China.
authors.forename: Bin Bin
authors.initials: BB
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China.
authors.forename: Hai Shan
authors.initials: HS
authors.lastname: Tian
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China.
authors.forename: Li Sha
authors.initials: LS
authors.lastname: Chi
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China.
authors.forename: Yuan Meng
authors.initials: YM
authors.lastname: Duan
authors.affiliation: The Affiliated Wenling Hospital of Wenzhou Medical University, Wenling, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China.
authors.forename: Zhong Xin
authors.initials: ZX
authors.lastname: Zhu
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China.
authors.forename: Wan Hui
authors.initials: WH
authors.lastname: Cai
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China.
authors.forename: Yu Ting
authors.initials: YT
authors.lastname: Zhu
authors.affiliation: The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.
authors.forename: Tie Min
authors.initials: TM
authors.lastname: Wei
authors.affiliation: Department of Biology, Stanford University, Stanford, California, United States of America.
authors.forename: Hong Bo
authors.initials: HB
authors.lastname: Ye
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China.
authors.forename: Wei Tao
authors.initials: WT
authors.lastname: Cong
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, China.
authors.forename: Li Tai
authors.initials: LT
authors.lastname: Jin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D016222:Fibroblast Growth Factor 2; D048670:MAP Kinase Kinase 4; D005947:Glucose