Effects of Statins on Heme Oxygenase-1 Regulation

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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