Jiang Yucheng, Zheng Zhaozheng, Wang JunYi, Liao Yingjie, Jia Zhihan, Lin Wante, Xu Diyun, Wang Jiong, Wu Gaojun, Liang Guang, Ye Bozhi
Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Inflammopharmacology. 2025 Mar 27. doi: 10.1007/s10787-025-01721-1.
Vascular injury is a serious complication associated with hypertension, for which effective treatments are currently lacking. Oxidative stress serves as the primary pathophysiological mechanism underlying hypertension-induced vascular injury. Carnosol, an extract derived from rosemary, has garnered increasing interest because of its well-established antioxidant properties. However, its potential therapeutic effect on vascular injury remains unclear. This study investigated the therapeutic potential of carnosol in angiotensin II-stimulated vascular injury and elucidated its underlying mechanisms of action. C57BL/6J mice were subjected to vascular injury through the subcutaneous implantation of a micropump filled with Ang II, followed by the intragastric administration of carnosol for four weeks. Carnosol ameliorated Ang II-stimulated vascular dysfunction and remodeling in a dose-dependent manner. Mechanistically, carnosol exerted an inhibitory effect on oxidative stress in the vascular tissue and HUVECs by regulating the PI3K/AKT pathway. Furthermore, we revealed that FAK, which received the highest target score in the molecular docking analysis, could directly bind to carnosol in both cellular models and human aortic tissues. Additionally, carnosol inhibited the phosphorylation of FAK, thereby reducing oxidative stress levels in HUVECs. Notably, when PND-1186 was administered to inhibit the phosphorylation of FAK, carnosol was no longer able to modulate the PI3K/AKT signaling pathway. In conclusion, we showed that carnosol can inhibit the PI3K/AKT signaling pathway by binding to the FAK protein and reducing its phosphorylation, thereby improving Ang II-stimulated vascular injury.
血管损伤是与高血压相关的一种严重并发症，目前缺乏有效的治疗方法。氧化应激是高血压诱导的血管损伤的主要病理生理机制。鼠尾草酸是一种从迷迭香中提取的物质，因其具有公认的抗氧化特性而受到越来越多的关注。然而，其对血管损伤的潜在治疗作用仍不清楚。本研究探讨了鼠尾草酸对血管紧张素II刺激的血管损伤的治疗潜力，并阐明了其潜在的作用机制。通过皮下植入充满血管紧张素II的微型泵使C57BL/6J小鼠遭受血管损伤，随后对其进行四周的鼠尾草酸性胃给药。鼠尾草酸以剂量依赖性方式改善血管紧张素II刺激的血管功能障碍和重塑。从机制上讲，鼠尾草酸通过调节PI3K/AKT途径对血管组织和人脐静脉内皮细胞（HUVECs）中的氧化应激发挥抑制作用。此外，我们发现，在分子对接分析中获得最高靶点评分的黏着斑激酶（FAK），在细胞模型和人主动脉组织中均可直接与鼠尾草酸结合。此外，鼠尾草酸抑制FAK的磷酸化，从而降低HUVECs中的氧化应激水平。值得注意的是，当给予PND-1186以抑制FAK的磷酸化时，鼠尾草酸不再能够调节PI3K/AKT信号通路。总之，我们表明，鼠尾草酸可通过与FAK蛋白结合并减少其磷酸化来抑制PI3K/AKT信号通路，从而改善血管紧张素II刺激的血管损伤。
