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dc.contributor.advisorShi, Honglian
dc.contributor.authorZhang, Ziyan
dc.date.accessioned2016-10-11T16:28:26Z
dc.date.available2016-10-11T16:28:26Z
dc.date.issued2014-08-31
dc.date.submitted2014
dc.identifier.otherhttp://dissertations.umi.com/ku:13572
dc.identifier.urihttp://hdl.handle.net/1808/21640
dc.description.abstractStroke is a major cause of death and the leading cause of long-term disability in industrialized countries. Ischemic stroke-induced brain injury results from the interaction of complex pathophysiological processes, including energy failure, calcium overload, excitotoxicity, oxidative stress, disruption of blood-brain barrier (BBB) and inflammation. Despite the wealth of knowledge regarding the cellular and molecular mechanisms underlying neuronal death after stroke, research for several decades has failed to develop an effective and safe neuroprotective treatment. One complicating factor in the development of neuroprotective strategies is the dual nature of many of the processes that occur in the brain during stroke. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of cellular and tissue adaption to hypoxia. It plays both protective and detrimental roles in ischemic stroke by inducing a wide array of target genes involved in angiogenesis, erythropoiesis, cell survival/death, and energy metabolism. The dual face of HIF-1 in the pathophysiology of cerebral ischemia is postulated to partially depend on thedifferent functions of its target proteins in specific type of brain cells. In the current studies, we hypothesize that neuronal HIF-1 accumulation is protective whereas endothelial HIF-1 induction is implicated in BBB disruption. We first evaluated HIF-1's role in the antioxidant N-acetylcysteine (NAC)-mediated neuroprotection in a transient cerebral ischemia animal model. The study demonstrated that pre-treatment of NAC increased the neuronal expression of HIF-1α, the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3 in the ischemic brain of rodents subjected to 90 min middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Suppressing HIF-1 activity by pharmacological inhibitorsor by specific knock-out neuronal HIF-1α abolished NAC's neuroprotective effects. Furthermore, we observed that NAC increased HIF-1α stability through enhancingits interaction with heat-shock protein 90 (Hsp90) in ischemic brains. Increased BBB permeability and associated cerebral edema formation are potentially lethal complications of ischemic stroke. Accumulating evidence has shown that admission hyperglycemia in conjunction with ischemia/reperfusion causes exacerbated cerebrovascular endothelial cell dysfunction and increased BBB permeability, which leads to augmented brain edema and hemorrhagic transformation in ischemic stroke.The hypothesis of the second part of this dissertation is that endothelial HIF-1 is implicated in hyperglycemia-exacerbated BBB disruption after ischemia. Both in vitro and in vivo studies were undertaken to investigate the effect of hyperglycemia on (1) HIF-1α and its target genes expression; (2) ischemia-induced BBB permeability change; and (3) the effect of HIF-1α inhibition on BBB permeability after ischemia. The in vitrostudy showed that high glucose enhanced HIF-1αand its downstream factors expression in the endothelial cell culture after oxygen glucose deprivation (OGD)/reoxygenation. This was correlated withan increased paracellular permeability as well as diminished expression and disrupted continuity of tight junction (TJ) proteins. Suppressing HIF-1 activity by HIF-1α inhibitors ameliorated the alterations in paracellular permeability and expression and distribution pattern of TJ proteins induced by high glucose exposure. In in vivo studies, diabetic mice subjected to 90 min MCAOfollowed by reperfusiondemonstrated higher expression of HIF-1α and its target gene vascular endothelial growth factor (VEGF) in the ischemic brain microvessels than non-diabetic control mice. Diabetic mice also showed exacerbated BBB damage and TJ disruption, increased infarct volume, and worsened neurological deficits. SuppressingHIF-1 activity by specific knock-out endothelial HIF-1α ameliorated BBB leakage and brain infarction in diabetic animals. Taken together, these present studies provide new information concerning HIF-1's function in experimental models of acute ischemic stroke. Neuronal HIF-1α is an important mediator of antioxidant NAC's neuroprotective effect in ischemic stroke, whereas endothelial HIF-1α is involved in hyperglycemia-induced BBB breakdown after cerebral ischemia. The results suggest that developing therapeutic strategies by targeting HIF-1 needs to consider its multifunctional roles and differential effects on different cell types.
dc.format.extent230 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectPharmacology
dc.subjectblood-brain barrier
dc.subjectHIF-1
dc.subjecthyperglycemia
dc.subjectischemic stroke
dc.subjectN-acetylcysteine
dc.subjectneuroprotection
dc.titleThe Dual Role of Hypoxia-Inducible Factor-1 in Ischemic Stroke: Neuroprotection and Blood-Brain Barrier Disruption
dc.typeDissertation
dc.contributor.cmtememberDobrowsky, Rick T
dc.contributor.cmtememberMichaelis, Elias K
dc.contributor.cmtememberYan, Shidu
dc.contributor.cmtememberDing, Wenxing
dc.thesis.degreeDisciplinePharmacology & Toxicology
dc.thesis.degreeLevelPh.D.
dc.provenance04/05/2017: The ETD release form is attached to this record as a license file.
dc.rights.accessrightsopenAccess


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