Inhibition of glycogen synthase kinase-3beta improves tolerance to ischemia in hypertrophied hearts.
BACKGROUND
Hypertrophied myocardium is more susceptible to ischemia/reperfusion injury, in part owing to impaired insulin-mediated glucose uptake. Glycogen synthase kinase-3beta (GSK-3beta) is a key regulatory enzyme in glucose metabolism that, when activated, phosphorylates/inactivates target enzymes of the insulin signaling pathway. Glycogen synthase kinase-3beta is regulated upstream by Akt-1. We sought to determine whether GSK-3beta is activated in ischemic hypertrophied myocardium owing to impaired Akt-1 function, and whether inhibition with lithium (Li) or indirubin-3'-monoxime,5-iodo- (IMI), a specific inhibitor, improves post-ischemic myocardial recovery by improving glucose metabolism.


METHODS
Pressure-overload hypertrophy was achieved by aortic banding in neonatal rabbits. At 6 weeks, isolated hypertrophied hearts underwent 30 minutes of normothermic ischemia and reperfusion with or without a GSK-3beta inhibitor (0.1 mM Li; 1 microM IMI) as cardioplegic additives. Cardiac function was measured before and after ischemia. Expression, activity of Akt-1 and GSK-3beta, and lactate were determined at end-ischemia.


RESULTS
Contractile function after ischemia was better preserved in hypertrophied hearts treated with GSK-3beta inhibitors. Activity of Akt-1 was significantly impaired in hypertrophied myocardium at end-ischemia. Glycogen synthase kinase-3beta enzymatic activity at end-ischemia was increased in hypertrophied hearts and was blocked by Li or IMI concomitant with significantly increased lactate production, indicating increased glycolysis.


CONCLUSIONS
Regulatory inhibition of GSK-3beta by Akt-1 in hypertrophied hearts is impaired, leading to activation during ischemia. Inhibition of GSK-3beta by Li or IMI improves tolerance to ischemia/reperfusion injury in hypertrophied myocardium. The likely protective mechanism is an increase in insulin-mediated glucose uptake, resulting in greater substrate availability for glycolysis during ischemia and early reperfusion.
Barillas
Rodrigo
R
Department of Cardiac Surgery, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
Friehs
Ingeborg
I
Cao-Danh
Hung
H
Martinez
Joseph F
JF
del Nido
Pedro J
PJ
D000818:Animals; D001835:Body Weight; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006019:Glycolysis; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000503:physiopathology; D007211:Indoles / Q000627:therapeutic use*; D019344:Lactic Acid / Q000096:biosynthesis; D018020:Lithium Compounds / Q000627:therapeutic use*; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000201:enzymology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010091:Oximes / Q000627:therapeutic use*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits
D007211:Indoles; D018020:Lithium Compounds; D010091:Oximes; D047428:Protein Kinase Inhibitors; C474021:indirubin-3'-monoxime; D019344:Lactic Acid; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3