Abstract W P362: Krupple-Like Factor 11 Mediates Blood-Brain Barrier Dysfunction in Ischemic Stroke

The blood-brain barrier (BBB) is one of the primary targets of cerebral ischemic insults. Extensive studies have shown that breakdown of BBB integrity initiates a devastating cascade of events and eventual neuronal loss in cerebral ischemia. Thus, it is important to identify mechanisms by which loss of BBB integrity can be reduced under ischemic stroke conditions. Kruppel-like factors (KLF) are members of the zinc finger family of transcription factors and play key roles in cellular growth and differentiation. Up to now, the function of the KLF family in the cerebral vasculature is largely unexplored. KLF11 is a member of the KLF family with high expression in vascular endothelium. Mutations or variations in KLF11 gene are closely associated with human type 2 diabetes mellitus, a major risk factor for stroke. Previously, we have demonstrated that peroxisome proliferator-activated receptor γ-mediated cerebral vascular protection during ischemic insults needs recruitment of KLF11 as its critical coactivator. However, the functional significance and mechanisms of KLF11 itself in regulating cerebrovascular pathogenesis are totally unknown in ischemic stroke. Here we have shown that KLF11 expression is significantly decreased in the cerebral vasculature, cerebral cortex, and cultured BMECs after in vivo and in vitro ischemic stimuli. KLF11 genetic deficiency leads to increased BBB permeability in mouse brain after middle cerebral artery occlusion as well as increased leukocyte-endothelial rolling and adhesion in the vascular wall. Moreover, we also demonstrated that gain-of-KLF11 function by adenovirus can significantly inhibit BMEC death after exposure to Oxygen Glucose Deprivation. Mechanistically, we found several potential KLF11 binding sites in the promoter region of selective endothelial tight junctions. Genetic deletion of KLF11 in mice significantly reduced cerebral expression of Claudin 5 and ZO-1 mRNAs. These findings suggest that KLF11 functions as a novel master regulator in BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of KLF11-mediated BBB protection may lead us to discover novel pharmaceutical targets for the development of effective therapies against ischemic stroke.