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首页> 外文学位 >Crosstalk between Angiotensin II receptors and insulin receptor: A possible mechanism for the co-development of hypertension and insulin resistance.
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Crosstalk between Angiotensin II receptors and insulin receptor: A possible mechanism for the co-development of hypertension and insulin resistance.

机译：血管紧张素II受体和胰岛素受体之间的串扰：高血压和胰岛素抵抗共同发展的可能机制。

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摘要

Molecular analysis of the cross talk between Angiotensin II (Ang II) and insulin signaling systems reveal that they are multifaceted and occur at cellular level and intracellular level. Experiments were carried out to evaluate the crosstalk between the Ang II receptors-AT1 and AT2 and the Insulin Receptor (IR) to understand the changes in the signaling pathway that could lead to the transition from hypertension to insulin resistance. Transient expression of rat AT2 in CHO cells induced co-immunoprecipitation of the AT2R with IRbeta and inhibition of IRbeta tyrosine phosphorylation. An AT2-peptide carrying the amino acids 226-363 (that spans 3rd intracellular loop (ICL) and C-terminal cytoplasmic domain) was sufficient for AT2- IRbeta interaction in a yeast two-hybrid assay. An orthovanadate-insensitive AT2-IRbeta association was also observed in human breast cancer cell line MCF-7. Interestingly, while AT2- IRbeta complex formation was insensitive to pertussis toxin (PTX), AT2-mediated inhibition of IRbeta phosphorylation was partially sensitive to PTX treatment in MCF-7.To address the mechanism behind the transition of an early hypertensive heart to an insulin resistant status, we investigated the changes that occur at post translational level in the IR and its downstream signaling molecules that modulate insulin signaling. Early hypertension was induced in 10-week old SD rats by 2% NaCl diet in combination with Ang II infusion. Enhanced serine phosphorylation of the IRbeta suggestive of dysfunctional insulin signaling was observed in cardiac tissues as a result of the treatment. In addition, an enhanced association of both AT1R and AT2R with IRbeta was observed in the heart tissue lysates from hypertensive rat heart.To evaluate the tissue effects of Ang II, we compared the transcriptome of hypertensive rat hearts to the controls. Analysis suggests that the Ang II induces multiple responses in heart tissue that result in changes to the gene expression pattern intended to promote insulin sensitivity and insulin resistance. Taken together our results suggest that exogenous Ang II and moderately high salt diet promote metabolic abnormalities in heart tissue that result in sequestration of IR and modulation of IR signaling, and significant changes in gene expression profile in the hypertensive heart.
机译：血管紧张素II（Ang II）和胰岛素信号传导系统之间的串扰的分子分析表明，它们是多方面的，并发生在细胞水平和细胞内水平。进行实验以评估Ang II受体AT1和AT2与胰岛素受体（IR）之间的串扰，以了解信号通路中可能导致从高血压到胰岛素抵抗转变的变化。大鼠AT2在CHO细胞中的瞬时表达诱导了AT2R与IRbeta的共免疫沉淀以及IRbeta酪氨酸磷酸化的抑制。带有氨基酸226-363（跨越第3个细胞内环（ICL）和C端胞质域）的AT2-肽足以在酵母双杂交检测中实现AT2- IRbeta相互作用。在人乳腺癌细胞系MCF-7中也观察到了原钒酸盐不敏感的AT2-IRbeta缔合。有趣的是，虽然AT2-IRbeta复合物的形成对百日咳毒素（PTX）不敏感，但AT2介导的IRbeta磷酸化抑制对MCF-7中的PTX治疗部分敏感。为了解决早期高血压心脏向胰岛素过渡的机制耐药状态，我们调查了IR及其下游调节胰岛素信号传导的信号分子在翻译后水平发生的变化。在10周龄SD大鼠中，通过2％NaCl饮食与Ang II输注相结合可诱发早期高血压。治疗的结果是在心脏组织中观察到IRβ的丝氨酸磷酸化增强，提示胰岛素信号功能异常。此外，在高血压大鼠心脏的心脏组织裂解物中，AT1R和AT2R与IRbeta的结合增强。为评估Ang II的组织作用，我们将高血压大鼠心脏的转录组与对照组进行了比较。分析表明，Ang II在心脏组织中诱导多种反应，从而导致旨在促进胰岛素敏感性和胰岛素抵抗的基因表达模式发生变化。总之，我们的结果表明，外源性Ang II和适度的高盐饮食会促进心脏组织的代谢异常，从而导致IR隔离和IR信号传导的调节，以及高血压心脏中基因表达谱的显着变化。

著录项

  • 作者

    Ramdas, Maya.;

  • 作者单位

    Mississippi State University.;

  • 授予单位 Mississippi State University.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 173 p.
  • 总页数 173
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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