ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1656473
Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice
Provisionally accepted
- 1Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 2Naval Medical University, Shanghai, China
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It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice (Mus musculus). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg−1·d−1, i.p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4g·kg−1·d−1), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice. In mice just after middle cerebral artery occlusion, intravenous injection of AKG-treated diabetic EPCs displayed a greater ability to promote local angiogenesis and reduce cerebral ischemic injury compared to injection of diabetic EPCs treated with vehicle. Furthermore, we found that AKG significantly increased the expression of manganese superoxide dismutase (MnSOD) and copper-zinc SOD (CuZnSOD), decreased intracellular O2·- levels, and attenuated inflammation in EPCs of diabetic mice. In cultured human umbilical vein endothelial cells (Homo sapiens, HUVECs), AKG (0.5 mM) rescued the functions of high glucose-stimulated HUVECs by reducing inflammation through the toll-like receptor 4 (TLR4)/nuclear factor kB (NF-κB) pathway and attenuating oxidative stress. In conclusion, AKG can enhance EPCs' angiogenic potential and protect against cerebral ischemic injury in diabetic mice. It is implied that chronic treatment with AKG may be a safe and promising option to prevent ischemic diseases (including stroke) in diabetes.
Keywords: diabetes, Alpha-ketoglutarate, endothelial progenitor cells, Angiogenesis, Cerebral ischemic injury
Received: 30 Jun 2025; Accepted: 03 Oct 2025.
Copyright: © 2025 Qiu, Ruan, Jiang, Shi, Tao, Chen, Peng and Xie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: He-Hui Xie, xhhtom@263.net
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