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Glycogen Synthase Kinase 3β Inhibitor Protects Against Vascular Hyperpermeability Following Hemorrhagic Shock
Author(s) -
Childs Ed W,
Hunter Felicia A,
Tharakan Binu,
Sawant Devendra A,
Smythe W. Roy
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.593.4
Subject(s) - adherens junction , extravasation , vascular permeability , albumin , intravital microscopy , gsk 3 , actin cytoskeleton , occludin , medicine , pharmacology , tight junction , chemistry , phosphorylation , pathology , cytoskeleton , microcirculation , cadherin , biochemistry , cell
Hemorrhagic shock (HS) disrupts the endothelial cell adherens junctions leading to vascular hyperpermeability. β‐Catenin is an integral component of the adherens junction complex which helps to maintain barrier integrity by binding to adjacent cells via VE cadherin and intracellularly to actin cytoskeleton. We hypothesized that inhibition of GSK‐3β that phosphorylates β‐catenin would attenuate vascular hyperpermeability. Our objective was to test GSK‐3β specific inhibitor SB216763 against hyperpermeability following HS. In rats HS was induced by withdrawing blood to reduce the MAP to 40 mmHg for 60 minutes followed by resuscitation. Rats were given SB216763 ten minutes prior to shock. To study vascular permeability, the rats were injected intravenously, with FITC‐albumin and its flux across the mesenteric post‐capillary venules were determined using intravital microscopy. Sham group showed minimal extravsation of FITC‐albumin in the extravascular space. HS group showed significant and time dependent increase in FITC‐albumin extravasation ( p <0.05). SB216763 (600μg/kg) significantly decreased HS‐induced FITC‐albumin extravasation ( p <0.05). β‐Catenin phosphorylation by GSK‐3β is an important mechanism that regulates vascular hyperpermeability following HS. GSK‐3β inhibitors may have therapeutic potential against vascular hyperpermeability following hemorrhagic shock.