Tianjin Key Laboratory of Metabolic Diseases, Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.
Br J Pharmacol. 2021 Apr;178(7):1524-1540. doi: 10.1111/bph.15378. Epub 2021 Feb 15.
Disturbed flow induces endothelial dysfunction and contributes to uneven distribution of atherosclerotic plaque. Emerging evidence suggests that harmine, a natural constituent of extracts of Peganum harmala, has potent beneficial activities. Here, we investigated if harmine has an atheroprotective role under disturbed flow and the underlying mechanism.
Mice of ApoE , LDLR , and endothelial cell (EC)-specific overexpression of yes-associated protein (YAP) in ApoE background were fed with a Western diet and given harmine for 4 weeks. Atherosclerotic lesion size, cellular composition, and expression of inflammatory genes in the aortic roots were assessed. HUVECs were treated with oscillatory shear stress (OSS) and harmine and also used for proteomic analysis.
Harmine retarded atherogenesis in both ApoE and LDLR mice by inhibiting the endothelial inflammatory response. Mechanistically, harmine blocked OSS-induced YAP nuclear translocation and EC activation by reducing phosphorylation of YAP at Y357. Overexpression of endothelial YAP blunted the beneficial effects of harmine in mice. Proteomic study revealed that protein tyrosine phosphatase non-receptor type 14 (PTPN14) could bind to YAP. Moreover, harmine increased PTPN14 expression by stabilizing its protein level and inhibiting its degradation in proteasomes. PTPN14 knockdown blocked the effects of harmine on YAP and EC activation. Finally, overexpression of PTPN14 mimicked the effects of harmine and ameliorated atherosclerosis, and knockdown of PTPN14 blunted the atheroprotective effects of harmine and accelerated atherosclerosis, in a partial ligation mouse model.
Harmine alleviated OSS-induced EC activation via a PTPN14/YAP pathway and had a potent atheroprotective role.
血流紊乱会导致内皮功能障碍，并导致动脉粥样硬化斑块分布不均。新出现的证据表明，哈尔明，骆驼蓬的提取物中的一种天然成分，具有强大的有益活性。在这里，我们研究了哈尔明在血流紊乱下是否具有抗动脉粥样硬化作用及其潜在机制。
载脂蛋白 E（ApoE）、低密度脂蛋白受体（LDLR）和内皮细胞（EC）中 yes 相关蛋白（YAP）过表达的小鼠喂食西方饮食，并给予哈尔明 4 周。评估主动脉根部粥样硬化病变大小、细胞组成和炎症基因表达。用振荡剪切力（OSS）和哈尔明处理 HUVECs，也用于蛋白质组学分析。
哈尔明通过抑制内皮炎症反应，延缓了 ApoE 和 LDLR 小鼠的动脉粥样硬化形成。从机制上讲，哈尔明通过减少 YAP 在 Y357 处的磷酸化，阻止了 OSS 诱导的 YAP 核易位和 EC 激活。内皮细胞 YAP 的过表达削弱了哈尔明在小鼠中的有益作用。蛋白质组学研究表明，蛋白酪氨酸磷酸酶非受体 14（PTPN14）可以与 YAP 结合。此外，哈尔明通过稳定其蛋白水平和抑制其在蛋白酶体中的降解来增加 PTPN14 的表达。PTPN14 敲低阻断了哈尔明对 YAP 和 EC 激活的作用。最后，PTPN14 的过表达模拟了哈尔明的作用，改善了动脉粥样硬化，而 PTPN14 的敲低削弱了哈尔明的抗动脉粥样硬化作用，并加速了部分结扎小鼠模型中的动脉粥样硬化。
哈尔明通过 PTPN14/YAP 通路缓解了 OSS 诱导的 EC 激活，具有强大的抗动脉粥样硬化作用。
