Effects of Statins on Heme Oxygenase-1 Regulation

抗氧化防御蛋白血红素氧合酶-1（HO-1）是近年来出现的一种重要的抗氧化防御蛋白， 组织保护和抗炎作用的扩张剂。HO-1的细胞保护功能已被证实。 在各种组织中，包括脉管系统、心脏、肾脏和神经细胞中形成。HO-1是一种诱导剂， 血红素氧化酶一种催化血红素降解的酶，导致胆红素、铁和碳的产生 一氧化碳（CO），它们又都是生物活性产物。胆红素在生理上具有很强的抗氧化作用， 逻辑浓度CO同样显示出产生抗凋亡和细胞保护作用， 此外，作为平滑肌松弛介质发挥作用。独特的组织保护组合 和平滑肌松弛特性使得HO-1成为治疗某些疾病的感兴趣的靶点， 怀孕已经表明，HO-1对于在子宫收缩期间保持人类子宫处于松弛状态至关重要。 怀孕此外，胎盘HO-1水平的降低似乎与早产风险的增加有关。 子痫因此，旨在适度增加HO-1组织表达的治疗策略可能是可行的。 有益于许多疾病状态，包括与妊娠和人类发育有关的疾病。怎么-- 然而，已知的HO-1诱导剂，如重金属或氧化应激介质，对组织是有害的。 不适合用于治疗目的。HMG-CoA还原酶抑制剂，广泛用于降脂 药物（他汀类）诱导HO-1表达，并因此降低氧化应激。因此，他汀类药物或其 衍生物在与HO-1表达不足相关的病理条件下可能具有治疗益处。 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，以研究体内他汀类药物依赖性HO-1诱导，具体而言， 确定哪些器官和组织响应增加HO-1表达。此外，我们将重新识别- HO-1启动子中的gion调节他汀类药物的反应性，通过使用HO-1- 衍生的缺失突变体。他汀类药物的体内效应将通过两种非侵入性试验进行监测：总 身体CO排泄，胆红素产生的指标;和生物发光成像（BLI），HO-1的指标 转录。来自这些体内测定的数据将与HO-1和HO-2 mRNA的体外测定相关联 以及蛋白质水平和总HO酶活性。这将是第一次共同努力， HO-1是他汀类药物的新治疗靶点，也是胰岛素不足条件下保护作用的介质。 高HO-1表达，如先兆子痫和其他妊娠相关疾病

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