The proteasome activator REGγ promotes diabetic endothelial impairment by inhibiting HMGA2-GLUT1 pathway.

Yifan Xie, Rifeng Gao, Yang Gao, Zheng Dong, Robb E Moses, Xiaotao Li, Junbo Ge

Translational research : the journal of laboratory and clinical medicine 2022 Aug

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Diabetic vascular endothelial impairment is one of the main causes of death in patients with diabetes lacking adequately defined mechanisms or effective treatments. REGγ, the 11S proteasome activator known to promote the degradation of cellular proteins in a ubiquitin- and ATP-independent manner, emerges as a new regulator in the cardiovascular system. Here, we found that REGγ was upregulated in streptozocin (STZ)-induced diabetic mouse aortic endothelium in vivo and high glucose (HG)-treated vascular endothelial cells (ECs) in vitro. REGγ deficiency ameliorated endothelial impairment in STZ-induced diabetic mice by protecting against a decline in cellular glucose uptake and associated vascular ECs dysfunction by suppressing high mobility group AT-hook 2 (HMGA2) decay. Mechanically, REGγ interacted with and degraded the transcription factor HMGA2 directly, leading to decreased HMGA2 transcriptional activity, subsequently lowered expression of glucose transporter type 1 (GLUT1), and reduced cellular glucose uptake, vascular endothelial dysfunction, and impaired diabetic endothelium. Ablation of endogenous GLUT1 or HMGA2 or overexpressing exogenous HMGA2 in vascular ECs significantly blocked or reestablished the REGγ-dependent action on cellular glucose uptake and vascular endothelial functions of HG stimulation in vitro. Furthermore, exogenously introducing HMGA2 improved diabetic mice endothelial impairment features caused by REGγ in vivo, thereby substantiating a REGγ-HMGA2-GLUT1 pathway in diabetic endothelial impairment. Our findings indicate that modulating REGγ-proteasome activity may be a potential therapeutic approach for diabetic disorders with endothelial impairment. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Yifan Xie, Rifeng Gao, Yang Gao, Zheng Dong, Robb E Moses, Xiaotao Li, Junbo Ge. The proteasome activator REGγ promotes diabetic endothelial impairment by inhibiting HMGA2-GLUT1 pathway. Translational research : the journal of laboratory and clinical medicine. 2022 Aug;246:33-48