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The role of the A2b adenosine receptor in vascular function.

机译:A2b腺苷受体在血管功能中的作用。

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摘要

Adenosine plays a central role in various vascular functions, although the importance of its different receptors in mediating these effects has not been fully elucidated. This thesis focuses on the role of the A2b adenosine receptor (A2bAR) in vascular and metabolic functions. The A2bAR controls inflammation via its expression in bone marrow cells, and we found that A2bAR knockout (KO) on C57BL background results in upregulation of vascular adhesion molecules. When subjected to high fat diet, these mice developed a Type II diabetic profile characterized by high blood glucose, impaired glucose clearance, increased levels of plasma insulin, fat to muscle ratio, leptin and lipids.;To assess this receptor's role in atherosclerosis, we generated A2bAR KO mice on an apolipoprotein E (ApoE) null background and subjected them to high-fat diet. Atherosclerosis measured by oil-red-o, histology, and ultrasound, was more pronounced in the absence of the A2bAR. This was associated with elevated levels of plasma cholesterol and triglycerides concentrated in very low density lipoprotein particles. A similar increase in lipids was observed in the liver, a phenotype typical of steatosis. A2bAR bone marrow (BM) signals post BM-transplantation had no effect on atherosclerosis. Gene expression analysis of A2bAR KO livers, confirmed by western blotting, pointed to elevated levels of the transcription factor sterol response element binding protein-1 (SREBP-1). Protein levels of the SREBP-1 targets, acetyl-CoA carboxylase and fatty acid synthase were also elevated in the livers of A2bAR KO. Pharmacological inhibition or activation of A2bAR in primary hepatocytes isolated from ApoE KO mice led to elevation or downregulation of SREBP-1, respectively. In vivo, adenoviral restoration of this receptor in the liver resulted in reduction of plasma triglycerides and cholesterol. This reduction was associated with decreased levels of acetyl-CoA carboxylase and fatty acid synthase.;This study is the first to highlight the significance of the A2bAR in regulating SREBP-1 levels and consequent development of hyperlipidemia and atherosclerosis, as well as to suggest a role for this receptor in Type II diabetes.
机译:腺苷在各种血管功能中起着核心作用,尽管尚未完全阐明其不同受体在介导这些作用中的重要性。本文主要研究A2b腺苷受体(A2bAR)在血管和代谢功能中的作用。 A2bAR通过其在骨髓细胞中的表达来控制炎症,我们发现C57BL背景上的A2bAR基因敲除(KO)导致血管粘附分子的上调。当接受高脂饮食时,这些小鼠表现出II型糖尿病特征,其特征为高血糖,葡萄糖清除受损,血浆胰岛素水平升高,脂肪与肌肉比例,瘦素和脂质的水平。为了评估该受体在动脉粥样硬化中的作用,我们在载脂蛋白E(ApoE)无效背景下产生了A2bAR KO小鼠,并对其进行了高脂饮食。在没有A2bAR的情况下,通过油红-o,组织学和超声测量的动脉粥样硬化更为明显。这与血浆胆固醇和甘油三酯水平升高(浓度极低的脂蛋白颗粒集中)有关。在肝脏中观察到脂质的类似增加,这是典型的脂肪变性表型。 BM移植后的A2bAR骨髓(BM)信号对动脉粥样硬化没有影响。 Western印迹证实A2bAR KO肝脏的基因表达分析指出,转录因子固醇反应元件结合蛋白-1(SREBP-1)的水平升高。在A2bAR KO的肝脏中,SREBP-1靶标,乙酰辅酶A羧化酶和脂肪酸合酶的蛋白质水平也升高。从ApoE KO小鼠分离的原代肝细胞中A2bAR的药理抑制或激活分别导致SREBP-1升高或下调。在体内,肝脏中该受体的腺病毒恢复导致血浆甘油三酸酯和胆固醇降低。这种减少与乙酰辅酶A羧化酶和脂肪酸合酶水平的降低有关。这项研究是第一个强调A2bAR在调节SREBP-1水平以及随后的高脂血症和动脉粥样硬化发展中的重要性的研究,并暗示该受体在II型糖尿病中的作用。

著录项

  • 作者

    Koupenova-Zamor, Milka S.;

  • 作者单位

    Boston University.;

  • 授予单位 Boston University.;
  • 学科 Biology Molecular.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 236 p.
  • 总页数 236
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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