Abstract 606: Myocardial Protection by Glycogen Synthase Kinase-3β Inhibition during Resuscitation from Cardiac Arrest
Background: GSK-3β functions as a “master switch” that is negatively regulated by various cardioprotective mechanisms. GSK-3β is upregulated by tyrosine 216 phosphorylation (P-Y216) and downregulated by serine 9 phosphorylation (P-S9). We investigated whether modulation of GSK-3β phosphorylation occurs during cardiac resuscitation and whether pharmacological GSK-3β inhibition improves post-resuscitation (PR) myocardial function.
Methods: Three groups of two rats each were randomized to 8 mins of untreated VF followed by 8 mins of closed-chest resuscitation and defibrillation or to sham intervention. Rats subjected to VF received a 0.6 mg/kg bolus of the GSK-3β inhibitor SB216763 (SB21) or 0.9% NaCl before chest compression. Hearts were harvested at 10 mins PR.
Results: Western blots with corresponding densitometries indexed to total GSK-3β are shown in Figure⇓. P-S9 increased in control rats (p = 0.052 vs sham) and further increased in SB21-treated rats (p = 0.024 vs sham). SB21 lessened PR myocardial dysfunction yielding significantly higher mean aortic pressure (109 ± 7 vs 79 ± 2 mmHg; p < 0.05) with numerically higher +dP/dtmax (5.1 ± 7 vs 3.5 ± 0.2 mmHg/sec x 103), cardiac index (108 ± 59 vs 76 ± 28 ml/min/kg) and left ventricular stroke work index (0.58 ± 0.24 vs 0.32 ± 0.11 mmHg x ml/kg).
Conclusions: Increased P-S9 independent of P-Y216 suggests activation of endogenous protective pathways that may downregulate GSK-3β activity. Pharmacological inhibition of GSK-3β further increased serine 9 phosphorylation state and lessened post-resuscitation myocardial dysfunction. Thus, GSK-3β may represent an important target for myocardial protection during resuscitation.