Exacerbated ischemic brain damage in type 2 diabetes via methylglyoxal-mediated miR-148a-3p decline

作者：Zhenguo Yang, Cheng Huang, Wenhui Huang, Chao Guo Yan, Xueyi Wen, Di Hu, Hesong Xie, Kejing He, Chi Kwan Tsang, Keshen Li · 发表于：BMC Medicine · 年份：2024 · DOI：10.1186/s12916-024-03768-3 · 被引用次数：12 · 研究领域：Advanced Glycation End Products research、MicroRNA in disease regulation、Neurological Disease Mechanisms and Treatments

BACKGROUND: Although microvascular dysfunction is a widespread phenomenon in type 2 diabetes (T2D) and is recognized as a main cause of T2D-aggravated ischemic stroke injury, the underlying mechanisms by which T2D-mediated exacerbation of cerebral damage after ischemic stroke is still largely uncharacterized. Here, we found that methylglyoxal-mediated miR-148a-3p decline can trigger blood-brain barrier dysfunction, thereby exacerbating cerebrovascular injury in diabetic stroke. METHODS: Using T2D models generated with streptozotocin plus a high-fat diet or db/db mice, and then inducing focal ischemic stroke through middle cerebral artery occlusion and reperfusion (MCAO/R), we established a diabetic stroke mouse model. RNA-sequencing was applied to identify the differentially expressed miRNAs in peri-cerebral infarction of diabetic stroke mice. RT-qPCR confirmed the potential miRNA in the plasma of ischemic stroke patients with or without T2D. Fluorescence in situ hybridization was used to image the localization of the miRNA. Brain pathology was analyzed using magnetic resonance imaging, laser-Doppler flowmetry, and transmission electron microscope in diabetic stroke mice. Immunofluorescence and immunoblotting were performed to elucidate the molecular mechanisms. RESULTS: miR-148a-3p level was downregulated in the peri-infarct cortex of stroke mice and this downregulation was even more enhanced in diabetic stroke mice. A similar decrease in miR-148a-3p expression was also conf...