The influence of tissue-specific heme oxygenase-1 (HO-1) deficiency on neuronal damage induced by subarachnoid hemorrhage in mice: the role of carbon monoxide (CO)

点击翻译按钮获取中文摘要

Endogenous production of carbon monoxide (CO) by heme oxygenase 1 (HO-1) represents an essential cellular protection mechanism. The importance of endogenous CO production is underlined by the facts that 1. deficiency of HO-1 in humans leads to a severe disease state with premature death, 2. classical genetic knockout of HO-1 in animals results in markedly reduced life span, 3. overexpression or induction of HO-1 and exogenous application of CO exerts protective effects in various disease models. Our lab has recently shown that exogenous application of CO, either inhalative or via systemic routes by a CO releasing molecule (CO-RM) exerts neuroprotective effects. Two important aspects remain unclear: 1. What is the distinct role of cell-specific HO-1 expression? 2. Does exogenous CO application equal endogenously generated CO by HO-1 induction regarding its protective effects? To answer these questions, we will use a well established model of cerebral injury (subarachnoid hemorrhage, SAH), in which HO-1 is upregulated and has been shown to be protective. With HO-1 knockout mice either with global HO-1 deficiency or conditional tissue-specific HO-1 deficiency in either endothelial, neuronal or microglial cells, we want to characterize the distinct protective role exerted by HO-1 expression in these cells. We therefore will study the following hypotheses: 1. HO-1 expression ameliorates neuronal injury after SAH. Specific aim 1: To evaluate the effect of global HO-1 deficiency on neuronal cell injury following SAH. 2. Endothelial-specific HO-1 is protective in SAH-induced cerebral vasospasm and endothelial dysfunction in mice. Specific aim 2: To evaluate the contribution of endothelial HO-1 deficiency to neuronal cell death following SAH. 3. Neuron-specific HO-1 prevents cell death following SAH in mice. Specific aim 3: To evaluate the effect of tissue-specific neuronal HO-1 knockout on neuronal cell death following SAH. 4. Microglia-specific HO-1 modulates heme removal and the SAH-induced neuroinflammatory response. Specific aim 4: To evaluate the contribution of microglia-specific HO-1 knockout to neuronal cell death following SAH. 5. CO can compensate for the deficiency of endogenous CO production in the above-described global and tissue-specific HO-1 knockout mice. Specific aim 5: To investigate the potentially protective effect of exogenous application of CO, either inhaled as gas or through the CO releasing molecule (CO-RM) ALF186 on neuronal damage after SAH in HO-1 deficient mice.