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：
7612500
负责人：
DAVID K STEVENSON
金额：
$ 8.76万
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/7612500
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

The antioxidant defense protein heme oxygenase-1 (HO-1) has emerged in recent years as an important me- diator of tissue protective and anti-inflammatory actions. Cytoprotective functions of HO-1 have been docu- mented in a variety of tissues including the vasculature, heart, kidney, and neuronal cells. HO-1 is an induc- ible 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 physio- logical 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. How- ever, known inducers of HO-1, such as heavy metals or mediators of oxidative stress, are detrimental to tis- sues 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 ex- pression. 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 re- gions 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 insuffi- cient HO-1 expression such as pre-eclampsia and other pregnancy-related disorders

近年来，抗氧化防御蛋白血红素加氧酶-1 (HO-1) 已成为一种重要的机制。组织保护和抗炎作用的调节剂。 HO-1 的细胞保护功能已被证实存在于多种组织中，包括脉管系统、心脏、肾脏和神经元细胞。 HO-1 是一种诱导催化血红素降解的酶，导致胆红素、铁和碳的生成一氧化碳 (CO)，它们又都是生物活性产品。胆红素在生理上发挥强大的抗氧化作用逻辑浓度。 CO 同样被证明可以产生抗凋亡和细胞保护作用，并且，此外，还起到平滑肌松弛介质的作用。组织保护的独特组合和平滑肌松弛特性使 HO-1 成为治疗某些疾病的有趣靶点怀孕。研究表明，HO-1 对于在怀孕期间保持人类子宫处于放松状态至关重要。怀孕。此外，胎盘 HO-1 水平降低似乎与预产期风险较高相关。子痫。因此，旨在适度增加 HO-1 组织表达的治疗策略可能是对许多疾病状态有益，包括与怀孕和人类发育有关的疾病状态。如何- 迄今为止，已知的 HO-1 诱导剂，例如重金属或氧化应激介质，对组织有害。起诉且不适合治疗目的。 HMG-CoA还原酶抑制剂，广泛用于降脂药物（他汀类药物）可诱导 HO-1 表达，从而减少氧化应激。因此，他汀类药物或它们的衍生物可能在与 HO-1 ex-不足相关的病理条件下具有治疗益处压力。在这个项目中，我们将使用转基因 (Tg) 小鼠，其中转基因由 HO-1 启动子组成与荧光素酶报告基因融合，研究体内他汀类药物依赖性 HO-1 诱导，特别是确定哪些器官和组织对 HO-1 表达增加做出反应。此外，我们将确定重新 HO-1 启动子中的 gions 通过使用体内转染 HO-1- 的小鼠来调节他汀类药物的反应性衍生的缺失突变体。他汀类药物的体内作用将通过两种非侵入性测定进行监测：体内二氧化碳排泄，胆红素产生的指标；和生物发光成像 (BLI)，HO-1 的指数转录。这些体内测定的数据将与 HO-1 和 HO-2 mRNA 的体外测定相关以及蛋白质水平和总 H2O 酶活性。这将是首次共同努力界定其角色 HO-1作为他汀类药物的新治疗靶点和在剂量不足的情况下发挥保护作用的介质古老的 HO-1 表达，例如先兆子痫和其他妊娠相关疾病