Prolonged ischemia can result in apoptotic death of vascular endothelial cells and lead to ischemic vascular diseases including vascular dementia, arteriosclerosis and brain oedema. Finding protective strategies to prevent this is therefore an urgent mission. Recent studies have shown that dysregulation of microRNAs (miRNAs) can lead to imbalance of Bcl-2 family proteins and mitochondrial dysfunction, leading to further damage of vascular cells under ischemic conditions. However, whether miRNAs can be used as a drug target for treating vascular diseases is not fully understood. In this study, we observed that the natural product 2,4,5-trihydroxybenzaldehyde (TDB) could effectively inhibit vascular cell apoptosis following oxygen-glucose deprivation/reperfusion (OGD/R) by maintaining mitochondrial membrane potential (MMP) and suppressing activation of the mitochondria-dependent caspase-9/3 apoptosis pathway. Furthermore, we identified miR-34a, a crucial negative regulator of Bcl-2, as a target for the protective effect of TDB on vascular cells. TDB-induced suppression of miR-34a resulted in a significant upregulation of Bcl-2 protein, MMP maintenance, and the survival of vascular cells following OGD/R. Our findings suggest that targeting miR-34a with the natural product TDB may provide a novel strategy for the treatment of ischemic vascular injuries, and demonstrate the therapeutic potential in targeting miRNAs using appropriate small molecules.

中文翻译：

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TDB通过靶向miR-34a增加Bcl-2表达来保护血管内皮细胞免受氧葡萄糖剥夺/再灌注诱导的损伤。

长时间的缺血可导致血管内皮细胞凋亡死亡，并导致缺血性血管疾病，包括血管性痴呆，动脉硬化和脑水肿。因此，寻找防止这种情况的保护性策略是当务之急。最近的研究表明，microRNA（miRNA）的失调可导致Bcl-2家族蛋白失衡和线粒体功能障碍，从而在缺血条件下导致血管细胞进一步受损。但是，尚未完全了解miRNA是否可以用作治疗血管疾病的药物靶标。在这项研究中，我们观察到天然产物2,4，5-三羟基苯甲醛（TDB）可以通过维持线粒体膜电位（MMP）和抑制线粒体依赖性caspase-9 / 3凋亡途径的激活来有效抑制氧-葡萄糖剥夺/再灌注（OGD / R）后血管细胞的凋亡。此外，我们确定了miR-34a（Bcl-2的关键负调节剂）作为TDB对血管细胞保护作用的靶标。TDB诱导的miR-34a抑制导致Bcl-2蛋白显着上调，MMP维持以及OGD / R后血管细胞的存活。我们的发现表明，以天然产物TDB靶向miR-34a可能为缺血性血管损伤的治疗提供一种新策略，并证明使用适当的小分子靶向miRNA的治疗潜力。