Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China.
Clin Exp Pharmacol Physiol. 2023 Oct;50(10):789-805. doi: 10.1111/1440-1681.13802. Epub 2023 Jul 10.
Diosmetin-7-O-β-D-glucopyranoside (Diosmetin-7-O-glucoside) is a natural flavonoid glycoside known to have a therapeutic application for cardiovascular diseases. Cardiac fibrosis is the main pathological change in the end stage of cardiovascular diseases. Endothelial-mesenchymal transformation (EndMT) induced by endoplasmic reticulum stress (ER stress) via Src pathways is involved in the process of cardiac fibrosis. However, it is unclear whether and how diosmetin-7-O-glucoside regulates EndMT and ER stress to treat cardiac fibrosis. In this study, molecular docking results showed that diosmetin-7-O-glucoside bound well to ER stress and Src pathway markers. Diosmetin-7-O-glucoside suppressed cardiac fibrosis induced by isoprenaline (ISO) and reduced the levels of EndMT, ER stress in mice heart. Primary cardiac microvascular endothelial cells (CMECs) were induced by transforming growth factor-β1 (TGF-β1) to perform EndMT. Diosmetin-7-O-glucoside could effectively regulate EndMT and diminish the accumulation of collagen I and collagen III. We also showed that the tube formation in CMECs was restored, and the capacity of migration was partially inhibited. Diosmetin-7-O-glucoside also ameliorated ER stress through the three unfolded protein response branches, as evidenced by organelle structure in transmission electron microscopy images and the expression of protein biomarkers like the glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). Further analysis showed that diosmetin-7-O-glucoside could suppress the expression level of Src phosphorylation, then block EndMT with the maintenance of endothelial appearance and endothelial marker expression. These results suggested that the diosmetin-7-O-glucoside can regulate EndMT through ER stress, at least in part via Src-dependent pathways.
香叶木素-7-O-β-D-吡喃葡萄糖苷（香叶木素-7-O-葡萄糖苷）是一种天然黄酮类糖苷，已知对心血管疾病具有治疗作用。心肌纤维化是心血管疾病终末期的主要病理改变。内质网应激（ER 应激）通过 Src 途径诱导的内皮-间充质转化（EndMT）参与心肌纤维化过程。然而，香叶木素-7-O-葡萄糖苷是否以及如何调节 EndMT 和 ER 应激以治疗心肌纤维化尚不清楚。在这项研究中，分子对接结果表明，香叶木素-7-O-葡萄糖苷与 ER 应激和 Src 途径标志物结合良好。香叶木素-7-O-葡萄糖苷抑制异丙肾上腺素（ISO）诱导的心肌纤维化，降低小鼠心脏中 EndMT 和 ER 应激水平。转化生长因子-β1（TGF-β1）诱导原代心肌微血管内皮细胞（CMECs）进行 EndMT。香叶木素-7-O-葡萄糖苷可有效调节 EndMT，减少胶原 I 和胶原 III 的积累。我们还表明，CMECs 的管形成得到恢复，迁移能力部分受到抑制。通过透射电镜图像中的细胞器结构和葡萄糖调节蛋白 78（GRP78）和 C/EBP 同源蛋白（CHOP）等蛋白生物标志物的表达，证明香叶木素-7-O-葡萄糖苷还通过三条未折叠蛋白反应分支改善 ER 应激。进一步分析表明，香叶木素-7-O-葡萄糖苷可以抑制 Src 磷酸化的表达水平，然后通过维持内皮外观和内皮标志物表达来阻断 EndMT。这些结果表明，香叶木素-7-O-葡萄糖苷可以通过 ER 应激调节 EndMT，至少部分通过 Src 依赖性途径。
