Paeoniflorin prevents endoplasmic reticulum stress-associated inflammation in lipopolysaccharide-stimulated human umbilical vein endothelial cells via the IRE1α/NF-κB signaling pathway,Food & Function

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Paeoniflorin prevents endoplasmic reticulum stress-associated inflammation in lipopolysaccharide-stimulated human umbilical vein endothelial cells via the IRE1α/NF-κB signaling pathway
Food & Function ( IF 5.1 ) Pub Date : 2018-03-21 00:00:00 , DOI: 10.1039/c7fo01406f
Juan Chen _{1,

2,

3,

4,

5} , Minghua Zhang _{4,

6,

7,

8} , Maomao Zhu _{4,

5,

9,

10,

11} , Junfei Gu _{4,

5,

9,

10} , Jie Song _{4,

5,

9,

10} , Li Cui _{4,

5,

9,

10} , Dan Liu _{4,

5,

9,

10} , Qing Ning _{4,

5,

9,

10} , Xiaobin Jia _{4,

12,

13,

14} , Liang Feng _{4,

12,

13,

14}

Affiliation

Endoplasmic reticulum (ER) stress-associated inflammation is a critical molecular mechanism involved in the pathogenesis of endothelial dysfunction (ED). Hence, strategies for alleviating ER stress-induced inflammation may be essential for the prevention of cardiovascular diseases. Paeoniflorin (PF), a bioactive compound from Paeonia lactiflora Pallas is known for its functional properties against vascular inflammation. However, to date, PF-mediated protection against ER stress-dependent inflammation has not been identified. Herein, we investigate the protective effect of PF on lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cell (HUVEC) injury and explore its underlying mechanism. The result of the cell viability assay indicates that PF promotes the cell survival rate in LPS-stimulated HUVECs. In addition, the LPS-induced over-production of inflammatory cytokines (interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1)) and ER stress markers (78 kDa glucose regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)) are significantly decreased by PF and the ER stress inhibitor 4-phenylbutric acid (4-PBA). The transmission electron microscopy (TEM) assay implies that the ultrastructural abnormalities in ER are reversed by PF treatment, which is similar to the protective effect of 4-PBA. Impressively, we find that the inositol-requiring enzyme 1α (IRE1α)/nuclear factor-kappa B (NF-κB) pathway is significantly activated and contributes to the progress of LPS-induced HUVEC injury by promoting inflammatory cytokine production. IRE1α siRNA, AEBSF (ATF6 inhibitor), GSK2656157 (PERK inhibitor), PDTC (NF-κB inhibitor) and thapsigargin (TG, IRE1 activator) are used to confirm the role of the IRE1α/NF-κB pathway in PF-mediated protection against LPS-induced HUVEC injury. Our findings indicate that PF has an inhibitory effect on endothelial injury. To summarize, PF might be a potential therapeutic agent to inhibit ER stress-associated vascular inflammation.

中文翻译：

eon药苷通过IRE1α/NF-κB信号通路防止脂多糖刺激的人脐静脉内皮细胞内质网应激相关的炎症

内质网（ER）应激相关炎症是内皮功能障碍（ED）发病机理中的关键分子机制。因此，减轻ER应激引起的炎症的策略对于预防心血管疾病可能是必不可少的。eon药（PF），一种来自Pa药的生物活性化合物Pallas以其抗血管炎症的功能特性而闻名。然而，迄今为止，尚未确定PF介导的针对ER应激依赖性炎症的保护作用。在这里，我们调查PF对脂多糖（LPS）刺激的人脐静脉内皮细胞（HUVEC）损伤的保护作用，并探讨其潜在机制。细胞活力测定的结果表明，PF促进了LPS刺激的HUVECs的细胞存活率。此外，LPS诱导的炎症细胞因子（白介素6（IL-6）和单核细胞趋化蛋白1（MCP-1））和ER应激标志物（78 kDa葡萄糖调节蛋白（GRP78）和CCAAT /增强子）的过量生产PF和ER应激抑制剂4-苯基丁酸（4-PBA）显着降低了结合蛋白同源蛋白（CHOP）的含量。透射电子显微镜（TEM）分析表明，通过PF处理可以逆转ER中的超微结构异常，这与4-PBA的保护作用相似。令人印象深刻的是，我们发现需要肌醇的酶1α（IRE1α）/核因子-κB（NF-κB）途径被显着激活，并通过促进炎症性细胞因子的产生而促进LPS诱导的HUVEC损伤的进展。IRE1αsiRNA，AEBSF（ATF6抑制剂），GSK2656157（PERK抑制剂），PDTC（NF-κB抑制剂）和毒胡萝卜素（TG，IRE1激活剂）用于确认IRE1α/NF-κB途径在PF介导的针对PF的保护中的作用。 LPS诱导的HUVEC损伤。我们的发现表明PF对内皮损伤具有抑制作用。综上所述，PF可能是抑制ER应激相关血管炎症的潜在治疗剂。

更新日期：2018-03-21

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