Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Pharmacol Res. 2022 May;179:106205. doi: 10.1016/j.phrs.2022.106205. Epub 2022 Apr 4.
Diabetic cardiovascular complications contribute more than half of diabetes mortality. Endothelial damage and subsequent pathological changes play a key role in this process. Phloretin, a plant-derived dihydrochalcone compound, was reported to have the activities in regulating metabolism homeostasis and anti-inflammation. However, its effects and the mechanism on early stage endothelial injury caused by diabetes are not clear yet. In our present study, human umbilical vein endothelial cells (HUVECs) were stimulated by high glucose or advanced glycation end products (AGEs) to induce endothelial damage, and streptozotocin (STZ) -induced diabetes mouse model was used for in vivo study. Our results showed that phloretin effectively reduced endothelial damage marker monocyte chemotactic protein-1 (MCP1) as well as pro-calcification factors bone morphogenetic protein-2 (BMP2) and receptor activator of NF-κB ligand (RANKL) expression, reversed the increased vimentin and decreased CD31 dose-dependently in vitro and in vivo. Phloretin had no effect on blood glucose level. However, it ameliorated endothelial injury and vascular fibrosis in diabetic mice. Further experiments revealed that phloretin could enhance AMP activated protein kinase (AMPK) activation and upregulate peroxidase proliferator activated receptor-gamma coactivator-lα (PGC1α) level, and inhibit the activation of TGFβ-Smad2-Snail signalling pathway which was abrogated by AMPK inhibitor, providing a rational mechanism that AMPK activation was required for the effects of phloretin on endothelial injury and endothelial-mesenchymal transformation (EndMT). Our data reveal a new role of phloretin in protection of diabetic endothelial damage via AMPK-dependent anti-EndMT activation, and also provide a potential therapeutic way for diabetic endothelial damage and its subsequent cardiovascular complications.
糖尿病心血管并发症导致超过一半的糖尿病患者死亡。内皮损伤及其随后的病理变化在这一过程中起着关键作用。根皮苷，一种植物来源的二氢查尔酮化合物，据报道具有调节代谢平衡和抗炎的作用。然而，其对糖尿病引起的早期内皮损伤的作用及其机制尚不清楚。在本研究中，我们用高葡萄糖或晚期糖基化终产物（AGEs）刺激人脐静脉内皮细胞（HUVECs），诱导内皮损伤，并使用链脲佐菌素（STZ）诱导的糖尿病小鼠模型进行体内研究。结果表明，根皮苷能有效降低内皮损伤标志物单核细胞趋化蛋白-1（MCP1）以及促钙化因子骨形态发生蛋白-2（BMP2）和核因子-κB 受体激活剂配体（RANKL）的表达，在体外和体内均能逆转高葡萄糖诱导的波形蛋白增加和 CD31 减少。根皮苷对血糖水平没有影响，但能改善糖尿病小鼠的内皮损伤和血管纤维化。进一步的实验表明，根皮苷可以增强 AMP 激活的蛋白激酶（AMPK）的激活，上调过氧化物酶体增殖物激活受体-γ共激活因子-1α（PGC1α）的水平，并抑制 TGFβ-Smad2-Snail 信号通路的激活，而 AMPK 抑制剂可以阻断这种激活，为根皮苷对内皮损伤和内皮-间充质转化（EndMT）的作用需要激活 AMPK 提供了合理的机制。我们的数据揭示了根皮苷通过 AMPK 依赖的抗 EndMT 激活来保护糖尿病内皮损伤的新作用，也为糖尿病内皮损伤及其随后的心血管并发症提供了一种潜在的治疗方法。
