Defective Endothelial Glutaminolysis Contributes to Impaired Angiogenesis and Poor Ischemic Tissue Repair in Diabetes

作者：Meina Zhao, Jiaheng Zhou, Yang Hu, Xinpei Wang, Jiong An, Meijie Liu, Pengfei Zhang, Xing Zhang, Jingwen Wang, Xing Jin, Miaomiao Xi, Jia Li · 发表于：Research · 年份：2025 · DOI：10.34133/research.0706 · 被引用次数：11 · 研究领域：Cancer, Hypoxia, and Metabolism、Mitochondrial Function and Pathology、Adipose Tissue and Metabolism

It has been demonstrated that glutamine is a key player in boosting endothelial cell (EC) proliferation. However, despite its importance, the role of endothelial glutaminolysis in diabetes remains largely unexplored. Our research aimed to investigate the function of glutaminolysis in ECs within the context of diabetes and to evaluate the potential therapeutic effects of salvianolic acid B (SalB) and α-ketoglutarate (α-KG) on diabetic vascular complications. Histological analysis of skin wounds in diabetic patients revealed delayed restoration of vascularization and collagen synthesis during wound healing, accompanied by decreased glutaminase 1 (GLS1) expression and reduced colocalization with the EC marker platelet-endothelial cell adhesion molecule-1 (CD31). Additionally, a significant decline in GLS1 activity and expression was observed in ECs isolated from diabetic hearts. In vitro studies using cultured ECs demonstrated that exposure to high glucose and high fat (HGHF) reduced GLS1 expression and suppressed glutaminolysis, impairing EC proliferation and tube formation. These adverse effects were mitigated by treatment with SalB or supplementation with α-KG plus nonessential amino acids (NEAAs). Among diabetic mice subjected to myocardial ischemia/reperfusion (MI/R), SalB administration or α-KG supplementation promoted myocardial revascularization and improved cardiac dysfunction. Notably, endothelial-specific GLS1 deletion in mice blocked the beneficial effects afforded b...