Cardioprotection by GSK-3 inhibition: role of enhanced glycogen synthesis and attenuation of calcium overload

Glycogen synthase kinase-3 (GSK-3) is a multi-functional kinase that regulates signalling pathways affecting glycogen metabolism, protein synthesis, mitosis, and apoptosis. GSK-3 inhibition limits cardiac ischaemia–reperfusion (IR) injury, but mechanisms are not clearly defined. This study tested the hypothesis that acute GSK-3 inhibition stimulates glycogen synthesis, repartitions glucose away from glycolysis, reduces proton (H⁺) production from glucose metabolism, and attenuates intracellular Ca²⁺ (Ca²⁺_i) overload.

In isolated perfused working rat hearts subjected to global ischaemia and reperfusion, the selective GSK-3 inhibitor, SB-216763 (SB, 3 µmol/L), when added either prior to ischaemia or at the onset of reperfusion, improved recovery of left-ventricular (LV) work. SB increased glycogen synthesis during reperfusion while glycolysis and H⁺ production were reduced. Rates of glucose and palmitate oxidation were improved by SB. Measurement of Ca²⁺_i concentration by rapid acquisition indo-1 fluorescence imaging showed that SB, when added either prior to ischaemia or at the onset of reperfusion, reduced diastolic Ca²⁺_i overload during reperfusion. In aerobic hearts depleted of glycogen by substrate-free perfusion to a level similar to that measured at the onset of reperfusion, SB accelerated glycogen synthesis and reduced glycolysis and H⁺ production independent of changes in LV work.

Our study indicates that reduction in H⁺ production by GSK-3 inhibition is an early and upstream event that lessens Ca²⁺_i overload during ischaemia and early reperfusion independent of LV work which enhances the recovery of post-ischaemic LV function and that may ultimately contribute to previously observed reductions in cell death and infarction.