Hyperglycemia Aggravates the Cerebral Ischemia Injury via Protein O-GlcNAcylation

Article type: Research Article

Authors: Zhu, Jing^{b; c; 1} | Ji, Xin^{a; c; 1} | Shi, Ruirui^c | He, Tianqi^{a; c} | Chen, Su-ying^d | Cong, Ruochen^d | He, Bosheng^d | Liu, Su^{b; *} | Xu, Hui^{c; *} | Gu, Jin-hua^{a; c; *}

Affiliations: [a] Department of Pharmacy, Affiliated Maternity & Child Healthcare Hospital of Nantong University, Medical School of Nantong University, Nantong, China | [b] Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China | [c] Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity & Child Healthcare Hospital of Nantong University, Nantong, China | [d] Department of Radiology, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu, China

Correspondence: [*] Correspondence to: Jin-hua Gu, Department of Pharmacy, Affiliated Maternity & Child Healthcare Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China. E-mail: jhgu@ntu.edu.cn; Hui Xu, Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity & Child Healthcare Hospital of Nantong University, Nantong 226007, China. E-mail: xuhui@ntu.edu.cn; Su Liu, Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China. E-mail: 327202278@qq.com.

Note: [1] These authors contributed equally to this work.

Abstract: Background:At least one-third of Alzheimer’s disease (AD) patients have cerebrovascular abnormalities, micro- and macro-infarctions, and ischemic white matter alterations. Stroke prognosis impacts AD development due to vascular disease. Hyperglycemia can readily produce vascular lesions and atherosclerosis, increasing the risk of cerebral ischemia. Our previous research has demonstrated that protein O-GlcNAcylation, a dynamic and reversible post-translational modification, provides protection against ischemic stroke. However, the role of O-GlcNAcylation in the exacerbation of cerebral ischemia injury due to hyperglycemia remains to be elucidated. Objective:In this study, we explored the role and underlying mechanism of protein O-GlcNAcylation in the exacerbation of cerebral ischemia injury caused by hyperglycemia. Methods:High glucose-cultured brain microvascular endothelial (bEnd3) cells were injured by oxygen-glucose deprivation. Cell viability was used as the assay result. Stroke outcomes and hemorrhagic transformation incidence were assessed in mice after middle cerebral artery occlusion under high glucose and streptozotocin-induced hyperglycemic conditions. Western blot estimated that O-GlcNAcylation influenced apoptosis levels in vitro and in vivo. Results:In in vitro analyses showed that Thiamet-G induces upregulation of protein O-GlcNAcylation, which attenuates oxygen-glucose deprivation/R-induce injury in bEnd3 cells cultured under normal glucose conditions, while aggravated it under high glucose conditions. In in vivo analyses, Thiamet-G exacerbated cerebral ischemic injury and induced hemorrhagic transformation, accompanied by increased apoptosis. While blocking protein O-GlcNAcylation with 6-diazo-5-oxo-L-norleucine alleviated cerebral injury of ischemic stroke in different hyperglycemic mice. Conclusion:Overall, our study highlights the crucial role of O-GlcNAcylation in exacerbating cerebral ischemia injury under conditions of hyperglycemia. O-GlcNAcylation could potentially serve as a therapeutic target for ischemic stroke associated with AD.

Keywords: Alzheimer’s disease, apoptosis, cerebral ischemia-reperfusion, hemorrhagic transformation, hyperglycemia, O-GlcNAcylation

DOI: 10.3233/JAD-230264

Journal: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 651-668, 2023