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Abnormally Elevated PKCδ Delays Diabetic Wound Healing by Inhibiting the GAD1-GABA Pathway
Peiliang Qin1,2, Peng Zhou1, Yating Huang1
1Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Backgruound:
Diabetic foot ulcer (DFU) is a challenging complication of diabetes mellitus, characterized by delayed wound healing. Protein kinase C delta (PKCδ) has been identified as an important factor in the pathogenesis of various diabetic complications, including DFU. However, the precise underlying mechanisms remain incompletely elucidated.
Methods:
Human umbilical vein endothelial cells (HUVECs) were cultured under high-glucose conditions, and PKCδ was knocked down using siRNA. The proliferation, migration, and tube formation of HUVECs were assessed. Metabolomic sequencing was performed to identify potential metabolites contributing to these changes. HUVEC proliferation, migration, tube formation, and apoptosis were then assessed after regulation of the selected metabolite. Finally, the effect of the metabolite on diabetic wound healing was evaluated.
Results:
In vitro, PKCδ knockdown upregulated glutamate decarboxylase 1 (GAD1) expression and gamma-aminobutyric acid (GABA) levels, which enhanced proliferation, migration, and tube formation and suppressed apoptosis of HUVECs under high glucose conditions. Interestingly, inhibition of GAD1 in normal glucose-treated HUVECs decreased proliferation, migration, and tube formation, and increased apoptosis. Furthermore, in vivo experiments demonstrated that topical administration of GABA accelerated the healing of diabetic wounds in streptozotocin-induced type 2 diabetes mellitus mice, as manifested by increased angiogenesis and proliferation.
Conclusion:
PKCδ-mediated inhibition of the GAD1-GABA pathway suppresses endothelial cell proliferation, migration, and tube formation and promotes apoptosis under high-glucose conditions, thereby delaying diabetic wound healing.
Insights
Protein kinase C delta (PKCδ) inhibition improves diabetic foot ulcer healing by upregulating the GAD1-GABA pathway, enhancing endothelial cell function and promoting wound closure.
Area of Science:
- Endocrinology
- Molecular Biology
- Wound Healing Research
Background:
- Diabetic foot ulcers (DFU) are a severe diabetes complication with impaired healing.
- Protein kinase C delta (PKCδ) plays a role in DFU pathogenesis, but mechanisms are unclear.
Purpose of the Study:
- To investigate the role of PKCδ in DFU pathogenesis.
- To elucidate the molecular mechanisms underlying PKCδ's effect on endothelial cells and wound healing.
Main Methods:
- Human umbilical vein endothelial cells (HUVECs) were cultured in high glucose with PKCδ knockdown.
- Metabolomics identified key metabolites.
- GAD1 and GABA levels were modulated.
- In vivo studies used diabetic mice with topical GABA treatment.
Main Results:
- PKCδ knockdown increased GAD1 and GABA, enhancing HUVEC proliferation, migration, and tube formation while reducing apoptosis.
- GABA accelerated diabetic wound healing in mice, increasing angiogenesis and proliferation.
- Inhibition of GAD1 impaired endothelial cell function.
Conclusions:
- PKCδ inhibition of the GAD1-GABA pathway impairs endothelial cell function under high glucose, delaying diabetic wound healing.
- The GAD1-GABA pathway is crucial for endothelial cell function and diabetic wound repair.
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