title: Role of Hypoxia Inducible Factor 1 in Hyperglycemia-Exacerbated Blood-Brain Barrier Disruption in Ischemic Stroke.
abstract: Diabetes is a major stroke risk factor and is associated with poor functional recovery after stroke. Accumulating evidence indicates that the worsened outcomes may be due to hyperglycemia-induced cerebral vascular complications, especially disruption of the blood-brain barrier (BBB). The present study tested a hypothesis that the activation of hypoxia inducible factor-1 (HIF-1) was involved in hyperglycemia-aggravated BBB disruption in an ischemic stroke model. Non-diabetic control and Streptozotocin-induced type I diabetic mice were subjected to 90min transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Our results demonstrated that hyperglycemia induced higher expression of HIF-1α and vascular endothelial growth factor (VEGF) in brain microvessels after MCAO/reperfusion. Diabetic mice showed exacerbated BBB damage and tight junction disruption, increased infarct volume as well as worsened neurological deficits. Furthermore, suppressing HIF-1 activity by specific knock-out endothelial HIF-1α ameliorated BBB leakage and brain infarction in diabetic animals. Moreover, glycemic control by insulin abolished HIF-1α up-regulation in diabetic animals and reduced BBB permeability and brain infarction. These findings strongly indicate that HIF-1 plays an important role in hyperglycemia-induced exacerbation of BBB disruption in ischemic stroke. Endothelial HIF-1 inhibition warrants further investigation as a therapeutic target for the treatment of stroke patients with diabetes.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, United States.
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, United States.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, United States. Electronic address: hshi@ku.edu.
authors.forename: Honglian
authors.initials: H
authors.lastname: Shi
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004195:Disease Models, Animal; D006943:Hyperglycemia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: BBB; HIF-1; diabetic stroke; hyperglycemia; insulin