Inhibition of glycogen synthase kinase-3β prevents activation of focal adhesion kinase after ischemia/reperfusion of the rat lung.
Recent studies on the mechanisms of ischemic preconditioning in myocardial tissue have presented convincing evidence that multiple protective pathways converge on inhibition of glycogen synthase kinase-3β (GSK-3β). To directly address the role of GSK-3β in ischemia and reperfusion (I/R) of the lung, a rat model of left lung in situ ischemia was used. The specific non-competitive inhibitor of GSK-3β, TDZD-8, was injected (3 mg/kg, vehicle in controls) 5 min before the left lung hilum was occluded for 60 min. Animals in the ischemia group underwent the same treatment, but without administration of TDZD-8. Lung functional and biochemical parameters were determined at time points 15 min and 60 min reperfusion. Treatment with TDZD-8 improved gas exchange (arterial pO2), but I/R-induced inflammation (plasma interleukin-6, leukocyte invasion) was not affected. The I/R cycle induced a rapid (15 min reperfusion) increase of protein tyrosine phosphorylation, including the activating phosphorylation of focal adhesion kinase at Tyr397, Tyr407, Tyr577, and Tyr861, and the non-receptor kinase Src at Tyr416. The phosphorylation was blocked by the GSK inhibitor. This effect may be related to the reduced plasma level of the strong effector of focal adhesion kinase, transforming growth factor-β1, in the TDZD group. The underlying mechanisms are elusive, but they deserve further investigation, especially in relation to the early increase of lung permeability in this rat model of I/R injury. In conclusion, the results suggest that inhibition of GSK-3β improves rat lung function during an I/R cycle, but only during the early reperfusion phase.
Clinic for Cardiac Surgery, University Hospital Dresden, Technical University Dresden, Dresden, Germany. t.waldow@herzzentrum-dresden.com
Thomas
T
Waldow
Wolfgang
W
Witt
Klaus
K
Matschke
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D013830:Thiadiazoles / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000378:metabolism
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D004791:Enzyme Inhibitors; D013830:Thiadiazoles; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3