Reperfusion after an ischemic stroke event is known to produce ROS that can cause neurovascular injury, BBB disruption with secondary vasogenic edema, and hemorrhagic transformation of infarcted brain tissue. Thus, ROS can restrict the benefits of tissue reperfusion with thrombolytic agents or mechanical devices in stroke patients. We have demonstrated that cerebral ischemia and reperfusion increase superoxide radicals in brain mitochondria, which leads to metalloproteinase-9 (MMP-9) activation and BBB disruption that characterize neurovascular injury and cerebral infarction. We have recently discovered that signal transducer and activator of transcription 3 (STAT3) is a transcription activator of the promoter of manganese-superoxide dismutase (SOD2). During reperfusion, the level of phosphorylated (activated) STAT3 and its recruitment to the SOD2 promoter are significantly reduced prior to reduction in SOD2 activity in ischemic neurons. We have also demonstrated that reduced SOD2 activity and oxidative stress will cause cerebral infarction, damage to the BBB, and intracerebral hemorrhagic transformation. Novel strategies that activate the STAT3 signaling pathway and up-regulation of SOD2 activity may be of significant translational and/or therapeutic value in limiting neurovascular injury after ischemic reperfusion. We have also demonstrated that hyperglycemia, a known stroke risk factor, exacerbated reperfusion injury by enhancing MMP-9 activation, BBB damage, and neuronal death by an oxidative stress mechanism that may involve NADPH oxidase (NOX2), a major cytosolic superoxide radical-producing enzyme. We now hypothesize that ischemic reperfusion causes down-regulation of STAT3 signaling and reduced SOD2 transcription and expression in neurovasculature, which will cause neurovascular dysfunction. Pre-existing hyperglycemia will exacerbate oxidative stress-mediated reperfusion injury by down-regulation of STAT3/SOD2 signaling and/or by up-regulation of NOX2 activity in endothelia and neurons. It is our aim to test these hypotheses using animal models with transient focal cerebral ischemia and with cell cultures for an in-depth mechanistic investigation.
Our specific aims are: 1) To investigate the role of oxidative stress and STAT3 signaling in neurovascular injury following ischemia/reperfusion (I/R) 2) To investigate the role of oxidative stress via NOX2 and STAT3/SOD2 signaling in hyperglycemia- mediated neurovascular injury following I/R 3) To investigate the interleukin-6 receptor as an upstream signal of STAT3 activation and its role in neurovascular protection in mice following I/R We believe that these are novel, but high-risk studies that will provide insights into translational and therapeutic opportunities to minimize oxidative stress-mediated neurovascular damage in patients who suffer acute ischemic stroke and reperfusion injury.
Nearly 80% of strokes are caused by occlusion of a cerebral artery, and early restoration of cerebral blood flow by reperfusion can salvage hyperfused brain tissue, thus limiting neurological dysfunction and enhancing behavioral recovery. However, reperfusion after cerebral ischemia produces reactive oxygen radicals that can damage the neurovasculature. Since the mechanism underlying this oxidative injury is not clear, with this application, we seek to elucidate this injurious mechanism and to provide therapeutic strategies to prevent or ameliorate brain injuries in stroke patients.
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