Effects of Statins on Heme Oxygenase-1 Regulation

他汀类药物对血红素加氧酶 1 调节的影响

基本信息

批准号：
7359601
负责人：
DAVID K STEVENSON
金额：
$ 23.37万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-20 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7359601
关键词：
Address Adult Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptotic Bilirubin Biological Assay Bioluminescence Blood - brain barrier anatomy Blood Vessels Carbon Monoxide Cells Clinical Trials Coenzyme A Condition Cyclic GMP Data Disease Endothelial Cells Enzymes Excretory function FVB Mouse Female Gas Chromatography Generations Genetic Polymorphism Genetic Transcription Heart Heavy Metals Heme Human Human Development Hydroxyl Radical Image In Vitro Iron Kidney Knock-out Laboratories Length Lipids Luciferases Measurement Mediator of activation protein Messenger RNA Monitor Mus Neurons Numbers Organ Oxidative Stress Oxidoreductase Oxis Patient currently pregnant Pharmaceutical Preparations Physiological Plasma Pre-Eclampsia Pregnancy Process Production Property Proteins Purpose Regulation Reporter Genes Risk Role Series Signal Pathway Smooth Muscle Soluble Guanylate Cyclase Stress Therapeutic Therapeutic Uses Tissues Transgenes Transgenic Mice Transgenic Organisms Uterus atorvastatin base enzyme activity heme oxygenase-1 in vitro Assay in vivo indexing inhibitor/antagonist interest lipophilicity mutant novel therapeutics promoter protective effect response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The antioxidant defense protein heme oxygenase-1 (HO-1) has emerged in recent years as an important mediator of tissue protective and anti-inflammatory actions. Cytoprotective functions of HO-1 have been documented in a variety of tissues including the vasculature, heart, kidney, and neuronal cells. HO-1 is an inducible enzyme that catalyzes the degradation of heme, leading to the generation of bilirubin, iron, and carbon monoxide (CO), which are, in turn, all bioactive products. Bilirubin exerts strong antioxidant effects at physiological concentrations. CO has likewise been shown to produce anti-apoptotic and cytoprotective actions and, in addition, to function as a smooth muscle relaxing mediator. The unique combination of tissue protective and smooth muscle relaxing properties makes HO-1 an interesting target for treatment of certain disorders in pregnancy. It has been shown that HO-1 is crucial for keeping the human uterus in a relaxed state during pregnancy. Moreover, a reduced level of placental HO-1 seems to be associated with a higher risk for pre-eclampsia. Thus, therapeutic strategies aimed at moderately increasing tissue expression of HO-1 might be beneficial in a number of disease states including those related to pregnancy and human development. However, known inducers of HO-1, such as heavy metals or mediators of oxidative stress, are detrimental to tissues and not suitable for therapeutic purposes. HMG-CoA reductase inhibitors, widely used as lipid-lowering drugs (statins), induce HO-1 expression and, as a consequence reduce oxidative stress. Thus, statins or their derivatives might be of therapeutic benefit under pathological conditions associated with insufficient HO-1 expression. In this project, we will use transgenic (Tg) mice where the transgene consists of the HO-1 promoter fused to the luciferase reporter gene to study statin-dependent HO-1 induction in vivo, and, specifically, to determine which organs and tissues respond with increased HO-1 expression. Moreover, we will identify regions in the HO-1 promoter that regulate statin responsiveness by using mice transfected in vivo with HO-1-derived deletion mutants. The in vivo effects of statins will be monitored by two noninvasive assays: total body CO excretion, an index of bilirubin production; and bioluminescence imaging (BLI), an index of HO-1 transcription. Data from these in vivo assays will be correlated with in vitro assays of HO-1 and HO-2 mRNA and protein levels and total HO enzyme activity. This will be the first concerted effort to delineate the role of HO-1 as a novel therapeutic target for statins and mediator of protective effects under conditions of insufficient HO-1 expression such as pre-eclampsia and other pregnancy-related disorders

描述（由申请人提供）：近年来，抗氧化剂防御蛋白血红素氧酶-1（HO-1）已成为组织保护性和抗炎作用的重要介体。 HO-1的细胞保护功能已在包括脉管系统，心脏，肾脏和神经元细胞在内的多种组织中进行了记录。 HO-1是一种可诱导的酶，可催化血红素的降解，导致胆红素，铁和一氧化碳（CO）的产生，这反过来又是所有生物活性产物。胆红素在生理浓度下施加强大的抗氧化作用。 CO同样被证明可以产生抗凋亡和细胞保护作用，此外还可以充当平滑的肌肉放松介体。组织保护和平滑肌肉放松特性的独特组合使HO-1成为治疗某些妊娠某些疾病的有趣目标。已经表明，HO-1对于在怀孕期间将人子宫保持在放松状态至关重要。此外，胎盘HO-1的水平降低似乎与益人前的风险更高有关。因此，旨在适度增加HO-1组织表达的治疗策略在许多疾病状态中可能是有益的，包括与妊娠和人类发育有关的疾病。但是，已知的HO-1诱导剂，例如重金属或氧化应激的介体，对组织有害，不适合治疗目的。 HMG-COA还原酶抑制剂，被广泛用作降脂药物（他汀类药物），诱导HO-1表达，因此减少了氧化应激。因此，在与HO-1表达不足有关的病理状况下，他汀类药物或其衍生物可能具有治疗益处。在这个项目中，我们将使用转基因小鼠，其中转基因由将HO-1启动子组成，将HO-1启动子与荧光素酶报告基因融合在一起来研究体内他汀类药物依赖性HO-1诱导，尤其是确定哪些器官和组织会随着HO-1表达的响应。此外，我们将通过使用带有HO-1衍生的缺失突变体的体内小鼠来调节他汀类药物反应性的HO-1启动子中的区域。他汀类药物的体内作用将通过两种无创测量来监测：总体CO排泄，胆红素产生的指数；和生物发光成像（BLI），HO-1转录的指数。来自这些体内测定的数据将与HO-1和HO-2 mRNA以及蛋白质水平以及总HO酶活性的体外测定相关。这将是将HO-1作为他汀类药物的新型治疗靶标的首次统一的努力，并在HO-1表达不足的情况下（例如前倾向和其他与妊娠有关的疾病）中的保护作用和保护作用介体。