Protective Role of Heme Oxygenase in Ischemic Brain

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A complication of stroke is cerebral hemorrhage. The heme oxygenase (HO) system, which plays a key role in cellular defense mechanisms, catalyses oxidation of hemoglobin heme to biologically active molecules: bile pigments and CO. We have identified two active forms of the enzyme: HO-1 and HO-2. HO-2 is a hemoprotein and may function as a "sink" for NO, an effector molecule in inflammation and immune response. We have developed transgenic (Tg) mice that overexpress HO-1 or HO-2. HO-1 Tg mice brain, when compared with nonTg mice, show increased neuronal cGMP levels and expression of HO-1 in the lining of blood vessels. And, after pMCAo, they show decreases in brain stroke volume and in lipid peroxidation. Also, Tg mice neurons are resistant to H2O2 and glutamate toxicity. Initial studies with the HO-2 Tg line show increase in neuronal HO-2 expression and decrease in brain lipid peroxidation. To date, no data are available on the effect of HO-2 overexpression on the outcome of stroke. Deletion of the gene, however, exacerbates such injury. Also, the effect of HO-1 gene transfer on CNS injury has not been examined. Although, upregulation of HO-1 gene expression, using adenovirus (Ad)-mediated gene transfer, is known to protect against oxidative stress-mediated systemic tissue injury. The overall objective of this proposal is to further explore the role of HO isozymes in neuronal protection against stroke and cerebral hemorrhage. Specific aims are: 1) Using the HO-1 and HO-2 Tg mice to investigate the effect of HO gene overexpression on the outcome of transient focal ischemia (tMCAo), and on subarachnoid hemorrhage (SAH) caused by injection of lysed blood into the subarachnoid space. The tMCAo model will be evaluated for progression of ischemic injury and markers of stress: lipid peroxidation and redox available iron; also, for heme and bilirubin levels. The SAH model will be evaluated for vasospasm and necrotic/ apoptotic cell death. 2) To evaluate in the above models the potential therapeutic benefits of Ad-HO-1 and Ad-HO-2 gene transfer in stroke and cerebral hemorrhage. Genes will be delivered by CSF or by intracarotid route and the same indeces will be evaluated.