Lubiprostone as a potential therapeutic agent to improve intestinal permeability and prevent the development of atherosclerosis in apolipoprotein E-deficient mice
Lubiprostone as a potential therapeutic agent to improve intestinal permeability and prevent the development of atherosclerosis in apolipoprotein E-deficient mice
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DOI：
10.1371/journal.pone.0218096
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发表时间：
2019-06-17
期刊：
影响因子：
3.7
通讯作者：
Tamura, Kouichi
中科院分区：
文献类型：
--
作者：
Arakawa, Kentaro;Ishigami, Tomoaki;Tamura, Kouichi
动脉粥样硬化和肠道微生物之间通过漏肠综合征（LGS）的相互作用尚未完全阐明，漏肠综合征（LGS）的特征在于肠通透性受损和将不期望的病原体引入体内。我们的目的是研究C1 C-2氯离子通道激活剂鲁比前列酮在载脂蛋白E缺陷（ApoE-/-）小鼠动脉粥样硬化发展中的潜在作用，据报道鲁比前列酮对LGS具有有益作用。在西方饮食（WD）的15周喂养期后，ApoE-/-小鼠用单独的西方型饮食（WD）或口服补充鲁比前列酮的WD处理10周。该喂养方案之后是LGS和主动脉中的动脉粥样硬化病变的实验评价。在鲁比前列酮小鼠中，与WD单独给药组相比，口服给药的4-kDa FITC-葡聚糖的体内易位显著改善，回肠中上皮紧密连接蛋白ZO-1和occludin的RNA表达显著上调，表明可能逆转WD诱导的肠屏障功能障碍。结果，WD引起的动脉粥样硬化病变形成的恶化在纵向开放的腹主动脉中减少了69%，在主动脉根部减少了26%。此外，循环免疫球蛋白水平显著降低，随后血管周围脂肪组织中的炎症反应减弱，如促炎细胞因子和趋化因子表达降低所证明。鲁比前列酮通过恢复肠屏障改善LGS诱导的炎症来减轻动脉粥样硬化。这些发现提高了靶向LGS治疗动脉粥样硬化的可能性。
The interaction between atherosclerosis and commensal microbes through leaky gut syndrome (LGS), which is characterized by impaired intestinal permeability and the introduction of undesired pathogens into the body, has not been fully elucidated. Our aim was to investigate the potential role of a ClC-2 chloride channel activator, lubiprostone, which is reported to have beneficial effects on LGS, in the development of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. After a 15-week feeding period of a Western diet (WD), ApoE-/- mice were treated with a Western-type diet (WD) alone or WD with oral supplementation of lubiprostone for 10 weeks. This feeding protocol was followed by experimental evaluation of LGS and atherosclerotic lesions in the aorta. In mice with lubiprostone, in vivo translocation of orally administered 4-kDa FITC-dextran was significantly improved, and RNA expression of the epithelial tight junction proteins, Zo-1 and occludin, was significantly up-regulated in the ileum, compared to the WD alone group, suggesting a possible reversal of WD-induced intestinal barrier dysfunction. As a result, WD-induced exacerbation of atherosclerotic lesion formation was reduced by 69% in longitudinally opened aortas and 26% in aortic root regions. In addition, there was a significant decrease in circulating immunoglobulin level, followed by an attenuation of inflammatory responses in the perivascular adipose tissue, as evidenced by reduced expression of pro-inflammatory cytokines and chemokines. Lubiprostone attenuates atherosclerosis by ameliorating LGS-induced inflammation through the restoration of the intestinal barrier. These findings raise the possibility of targeting LGS for the treatment of atherosclerosis.