Harmine alleviates atherogenesis by inhibiting disturbed flow-mediated endothelial activation via protein tyrosine phosphatase PTPN14 and YAP.
Harmine alleviates atherogenesis by inhibiting disturbed flow-mediated endothelial activation via protein tyrosine phosphatase PTPN14 and YAP.
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Harmine 通过蛋白酪氨酸磷酸酶 PTPN14 和 YAP 抑制血流介导的内皮细胞活化，从而减轻动脉粥样硬化形成。
DOI：
10.1111/bph.15378
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发表时间：
2021
影响因子：
7.3
通讯作者：
He Jinlong
中科院分区：
文献类型：
--
作者：
Yang Yujie;Ma Qiannan;Li Zhiyu;Wang Hui;Zhang Chenghu;Liu Yajin;Li Bochuan;Wang Yingmei;Cui Qinghua;Xue Fengxia;Ai Ding;Zhu Yi;He Jinlong
背景与目的血流紊乱导致内皮功能障碍，导致动脉粥样硬化斑块分布不均匀。新出现的证据表明，有害生物碱，一种天然成分的提取物的peganum harmala，有强大的有益活动。在这里，我们研究了在血流紊乱的情况下，鼠碱是否具有动脉粥样硬化保护作用及其潜在的机制。实验方法在ApoE−/−背景下，ApoE−/−、LDLR−/−和内皮细胞（EC）特异性过表达yes相关蛋白（YAP）的小鼠用西式饮食喂养，并给予鼠胺4周。评估动脉粥样硬化病变的大小、细胞组成和主动脉根部炎症基因的表达。HUVECs采用振荡剪切应力（OSS）和hammine处理，并用于蛋白质组学分析。沙明通过抑制内皮炎症反应延缓ApoE−/−和LDLR−/−小鼠动脉粥样硬化的发生。在机制上，毒鼠碱通过降低YAP在Y357位点的磷酸化来阻断OSS诱导的YAP核易位和EC激活。内皮细胞YAP的过度表达削弱了鼠胺的有益作用。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，毒草碱通过稳定PTPN14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敲除可阻断毒力对yapy357和EC激活的影响。最后，在部分结扎小鼠模型中，PTPN14的过表达模拟了鼠尾草碱和改善动脉粥样硬化的作用，而PTPN14的下调则减弱了鼠尾草碱的动脉粥样硬化保护作用和加速动脉粥样硬化。结论和意义沙明可通过PTPN14/ yapy357通路减轻OSS诱导的EC激活，并具有有效的动脉粥样硬化保护作用。
Background and PurposeDisturbed flow induces endothelial dysfunction and contributes to uneven distribution of atherosclerotic plaque. Emerging evidence suggests that harmine, a natural constituent of extracts ofPeganum harmala, has potent beneficial activities. Here, we investigated if harmine has an atheroprotective role under disturbed flow and the underlying mechanism.Experimental ApproachMice 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.Key ResultsHarmine 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 YAPY357and 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.Conclusion and ImplicationsHarmine alleviated OSS‐induced EC activation via a PTPN14/YAPY357pathway and had a potent atheroprotective role.