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

• 批准号: 7210136
• 负责人: DAVID K STEVENSON
• 金额: $ 19.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-20 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210136
• 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

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）：抗氧化防御蛋白血红素加氧酶-1（HO-1）近年来已成为组织保护和抗炎作用的重要介质。 HO-1 的细胞保护功能已在多种组织中得到证实，包括脉管系统、心脏、肾脏和神经元细胞。 HO-1 是一种诱导酶，可催化血红素降解，从而产生胆红素、铁和一氧化碳 (CO)，而这些又都是生物活性产物。胆红素在生理浓度下发挥强大的抗氧化作用。 CO 同样被证明可以产生抗凋亡和细胞保护作用，此外还可以作为平滑肌松弛介质。组织保护和平滑肌松弛特性的独特组合使 HO-1 成为治疗妊娠期某些疾病的有趣靶点。研究表明，HO-1 对于在怀孕期间保持人类子宫处于松弛状态至关重要。此外，胎盘 HO-1 水平降低似乎与先兆子痫风险较高相关。因此，旨在适度增加 HO-1 组织表达的治疗策略可能对许多疾病状态有益，包括与妊娠和人类发育相关的疾病状态。然而，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，不适合用于治疗目的。 HMG-CoA 还原酶抑制剂广泛用作降脂药物（他汀类药物），可诱导 HO-1 表达，从而减少氧化应激。因此，他汀类药物或其衍生物可能在与 HO-1 表达不足相关的病理条件下具有治疗益处。在这个项目中，我们将使用转基因 (Tg) 小鼠，其中转基因由与荧光素酶报告基因融合的 HO-1 启动子组成，以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，我们将通过使用体内转染 HO-1 衍生缺失突变体的小鼠来鉴定 HO-1 启动子中调节他汀类药物反应性的区域。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：全身二氧化碳排泄，胆红素产生的指数；和生物发光成像 (BLI)，HO-1 转录的指标。这些体内测定的数据将与 HO-1 和 HO-2 mRNA 和蛋白质水平以及总 HO 酶活性的体外测定相关。这将是第一次共同努力来描述 HO-1 作为他汀类药物的新治疗靶点和在 HO-1 表达不足的情况下（如先兆子痫和其他妊娠相关疾病）的保护作用介质的作用