High levels of plasma free fatty acids (FFAs) lead to endothelial dysfunction (ED), which is involved in the pathogenesis of Metabolic Syndrome, diabetes as well as atherosclerosis. ER stress and Endothelial-to-mesenchymal transition (EndMT) are demonstrated mechanistically related to endothelial dysfunction. Mesenchymal stem cells (MSCs) have exhibited an extraordinary cytoprotective effect on cellular lipotoxicity and vasculopathy. However, the underlying mechanisms have not been clearly defined. In the present study, we investigated whether MSCs could ameliorate palmitic acid (PA) - induced endothelial lipotoxicity by reducing ER stress and EndMT. We observed that MSCs coculture substantially alleviated PA-induced lipotoxicity in human umbilical vein endothelial cells (HUVECs). MSCs were able to restore the cell viability, increase tubule formation and migration ability, and decrease inflammation response and lipid deposition. Furthermore, PA caused endothelial to mesenchymal transition in HUVECs, which was abrogated by MSCs possibly through inhibiting ER stress. In addition, PA stimulated MSCs to secrete more stanniocalcin 1 (STC1). Knocking down of STC1 in MSCs attenuated their effects on PA-induced lipotoxicity in HUVECs. In vivo, MSCs transplantation alleviated dyslipidemia and endothelial dysfunction in high fat diet-fed SD rats. MSCs treated rats showed reduced expressions of ER stress-related genes in aortas, as well as suppressed expressions of EndMT-related proteins in rat aortic endothelial cells (RAECs). Overall, our findings indicated that MSCs were able to attenuate endothelial lipotoxicity through inhibiting ER stress and EndMT, in which STC1 secreted from MSCs may play a critical role.

中文翻译：

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间充质干细胞通过抑制内质网应激缓解棕榈酸诱导的内皮向间质转化

血浆游离脂肪酸（FFA）含量高会导致内皮功能障碍（ED），这与代谢综合征，糖尿病以及动脉粥样硬化的发病机理有关。内质网应激和内皮细胞向间充质转变（EndMT）被证明与内皮功能障碍有关。间充质干细胞（MSCs）对细胞的脂毒性和血管病变表现出非凡的细胞保护作用。但是，底层机制尚未明确定义。在本研究中，我们研究了MSC是否可以通过降低ER应激和EndMT来改善棕榈酸（PA）诱导的内皮脂毒性。我们观察到，MSCs共培养可显着减轻PA诱导的人脐静脉内皮细胞（HUVEC）的脂毒性。MSC能够恢复细胞活力，增加肾小管的形成和迁移能力，并减少炎症反应和脂质沉积。此外，PA导致HUVECs发生了由内皮向间质的转变，而MSCs可能通过抑制ER应力而将其消除。此外，PA刺激MSC分泌更多的锡钙蛋白1（STC1）。敲击MSCs中的STC1减弱了它们对PA诱导的HUVECs脂毒性的影响。在体内，MSCs移植可减轻高脂饮食喂养的SD大鼠的血脂异常和内皮功能障碍。MSCs处理的大鼠在主动脉中显示ER应激相关基因的表达减少，并且在大鼠主动脉内皮细胞（RAEC）中EndMT相关蛋白的表达被抑制。总体而言，我们的研究结果表明，MSC能够通过抑制ER应激和EndMT来减轻内皮脂毒性，