FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats.
FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats.
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DOI：
10.1371/journal.pone.0060653
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Cooke JP
中科院分区：
文献类型：
--
作者：
Ghebremariam YT;Yamada K;Lee JC;Johnson CL;Atzler D;Anderssohn M;Agrawal R;Higgins JP;Patterson AJ;Böger RH;Cooke JP
遗传学和药理学研究表明，一氧化氮合酶(NOS)途径的损伤与高血压和胰岛素抵抗(IR)有关。此外，内源性抑制剂不对称二甲基精氨酸(ADMA)对一氧化氮合酶的抑制也可能导致高血压和IR。另一方面，代谢ADMA的二甲基精氨酸二甲氨基水解酶(DDAH)在小鼠体内的过度表达与ADMA降低、NO增加和胰岛素敏感性增强有关。由于DDAH携带法尼醇X受体(FXR)反应元件，我们的目的是通过FXR激动剂INT-747上调其表达，并评估其对血压和胰岛素敏感性的影响。在这项研究中，我们评估了INT-747对盐敏感型高血压和胰岛素抵抗(Dahl-SS)Dahl大鼠组织DDAH表达和胰岛素敏感性的影响。我们的数据表明，高盐(HS)饮食显著增加了全身血压。此外，与赋形剂对照组相比，HS饮食下调了组织DDAH的表达，而INT-747保护了DDAH表达的丧失和胰岛素敏感性的增强。我们的研究可能为利用小分子调节DDAH的表达和/或活性来治疗IR的新方法提供基础。
Genetic and pharmacological studies have shown that impairment of the nitric oxide (NO) synthase (NOS) pathway is associated with hypertension and insulin-resistance (IR). In addition, inhibition of NOS by the endogenous inhibitor, asymmetric dimethylarginine (ADMA), may also result in hypertension and IR. On the other hand, overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes ADMA, in mice is associated with lower ADMA, increased NO and enhanced insulin sensitivity. Since DDAH carries a farnesoid X receptor (FXR)-responsive element, we aimed to upregulate its expression by an FXR-agonist, INT-747, and evaluate its effect on blood pressure and insulin sensitivity. In this study, we evaluated the in vivo effect of INT-747 on tissue DDAH expression and insulin sensitivity in the Dahl rat model of salt-sensitive hypertension and IR (Dahl-SS). Our data indicates that high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls. Our study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.
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影响因子：
3.5
作者：
Cooke, JP
通讯作者：
Cooke, JP
影响因子：
37.8
作者：
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DOI：
10.1124/jpet.109.153510
发表时间：
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发表时间：
2007-05-15
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