Protein tyrosine phosphatase 1B impairs diabetic wound healing through vascular endothelial growth factor receptor 2 dephosphorylation.
OBJECTIVE
Impaired wound healing is a major complication of diabetes mellitus. The mechanisms that govern wound healing, however, are complex and incompletely understood. In the present study, we determined the inhibitory role of protein tyrosine phosphatase 1B (PTP1B) in the process of diabetic wound healing.


RESULTS
First, by comparing the wound healing process in PTP1B knockout (PTP1B(-/-)) mice, ob/ob mice and their wild-type littermates in the presence or absence of streptozotocin treatment, we showed that the inhibition of mouse wound healing in streptozotocin-induced diabetic conditions is because of the upregulation and activation of PTP1B. Second, the impaired wound healing in ob/ob mice and streptozotocin-treated wild-type mice was rescued by a PTP1B inhibitor. Third, PTP1B, which is upregulated under hyperglycemic condition, inhibited the tube formation, proliferation, and migration of human microvascular endothelial cells induced by vascular endothelial growth factor, whereas this inhibition was largely abolished by the PTP1B inhibitor. Finally, mechanism study further indicated that PTP1B likely suppressed the proliferation, migration, and tube formation of vascular endothelial cells through dephosphorylation of vascular endothelial growth factor receptor 2.


CONCLUSIONS
Our study demonstrated that PTP1B negatively modulated the diabetic wound healing process by dephosphorylating the endothelial cell vascular endothelial growth factor receptor 2 and that the specific inhibitor of PTP1B might serve as a potential novel therapeutic tool for diabetic wound healing.
From the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China (J.Z., L.L., J.L., C.-Y.Z., Y.Z., K.Z.); and Department of Biology, Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta (Y.L.).
Jing
J
Zhang
From the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China (J.Z., L.L., J.L., C.-Y.Z., Y.Z., K.Z.); and Department of Biology, Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta (Y.L.).
Limin
L
Li
From the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China (J.Z., L.L., J.L., C.-Y.Z., Y.Z., K.Z.); and Department of Biology, Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta (Y.L.).
Jing
J
Li
From the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China (J.Z., L.L., J.L., C.-Y.Z., Y.Z., K.Z.); and Department of Biology, Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta (Y.L.).
Yuan
Y
Liu
From the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China (J.Z., L.L., J.L., C.-Y.Z., Y.Z., K.Z.); and Department of Biology, Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta (Y.L.). kzen@nju.edu.cn yjzhang@nju.edu.cn cyzhang@nju.edu.cn.
Chen-Yu
CY
Zhang
From the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China (J.Z., L.L., J.L., C.-Y.Z., Y.Z., K.Z.); and Department of Biology, Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta (Y.L.). kzen@nju.edu.cn yjzhang@nju.edu.cn cyzhang@nju.edu.cn.
Yujing
Y
Zhang
From the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China (J.Z., L.L., J.L., C.-Y.Z., Y.Z., K.Z.); and Department of Biology, Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta (Y.L.). kzen@nju.edu.cn yjzhang@nju.edu.cn cyzhang@nju.edu.cn.
Ke
K
Zen
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012883:Skin Ulcer / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
D004791:Enzyme Inhibitors; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
PTP1B protein, human; angiogenesis; effect; hyperglycemia; reactive oxygen species; vascular endothelial growth factor receptor-2, human; wound healing