Abstract
Delayed wound healing in diabetic patients is a serious diabetic complication, resulting in major health problems as well as high mortality and disability. The detailed mechanism still needs to be fully understood. In this study, we aim to investigate potential mechanisms and explore an efficient strategy for clinical treatment of diabetic wound healing. Human umbilical endothelial cells were exposed to hyperglycemia for 4 days, then switched to normoglycemia for an additional 4 days. The cells were harvested for the analysis of reactive oxygen species (ROS) generation, gene expression and VEGF signaling pathway. Furthermore, the diabetic wound model was established in rats for the evaluation of wound healing rates under the treatment of either ERβ agonist/antagonist or SOD mimetic MnTBAP. Our results show that transient hyperglycemia exposure results in persistent ROS overgeneration after the switch to normoglycemia, along with suppressed expression of ERβ, SOD2, and the VEGF signaling pathway. Either ERβ expression or activation diminishes ROS generation. In vivo experiments with diabetic rats show that ERβ activation or SOD mimetic MnTBAP diminishes ROS generation in tissues and accelerates diabetic wound healing. Transient hyperglycemia exposure induces ROS generation and suppresses ERβ expression, subsequently resulting in SOD2 suppression with additional elevated ROS generation. This forms a positive-feed forward loop for ROS generation with persistent oxidative stress. ERβ expression or activation breaks this loop and ameliorates this effect, thereby accelerating diabetic wound healing. We conclude that ERβ accelerates diabetic wound healing by ameliorating hyperglycemia-induced persistent oxidative stress. This provides a new strategy for clinical treatment of diabetic wound healing based on ERβ activation.
Highlights
Wound healing is involved with many tissues and factors, including endothelial cells, fibroblasts, and blood cells, together with many sequential process of inflammation, granulation formation and tissue remodeling
Our results indicate that expression of either Estrogen receptor β (ERβ) or mitochondrial superoxide dismutase (SOD2), or ERβ agonist treatment, diminishes hyperglycemia-induced persistent reactive oxygen species (ROS) generation
The results showed that hypoxia-inducible factor α (HIF1α) mRNA levels have no significant changes in different treatments, while the vascular endothelial growth factor (VEGF) mRNA levels decreased to 39% as a result of HG(4d)+LG(4d) treatment, and the infection of either ERβ lentivirus (↑ERβ) or SOD2 lentivirus (↑SOD2), or ERβ agonist DPN increased VEGF mRNA to 136, FIGURE 2 | ERβ expression diminishes hyperglycemia-induced persistent SOD2 suppression. (A,B) human umbilical vein endothelial cells (HUVEC) were incubated in hyperglycemia (25 mM glucose) for 4 days, and switched to normoglycemia (5 mM glucose) for an additional 4 days
Summary
Wound healing is involved with many tissues and factors, including endothelial cells, fibroblasts, and blood cells, together with many sequential process of inflammation, granulation formation and tissue remodeling. Diabetic foot ulcer (DFU) is one of the most serious diabetic complications that results from poor wound healing, which subsequently results in a major health problem in patients, causing high mortality and disability [2, 3]. Hyperglycemia-induced over-generation of reactive oxygen species (ROS) and subsequent oxidative stress is a major contributor to diabetic complications, as this ROS initiates many pathological signaling pathways, resulting in diabetic tissue damage [7,8,9]. SOD2 suppression results in increased ROS generation with subsequent mitochondrial dysfunction and oxidative stress [10, 11]; this may be one of the reasons for delayed wound healing in diabetic patients [12, 13]
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