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Inhibition of Phosphodiesterases Prevents Mitochondrial Permeability Transition Pore Opening by Inactivating GSK‐3β via PKA and PKG in Cardiac Cells

Both protein kinase A (PKA) and protein kinase G (PKG) can inactivate glycogen synthase kinase 3β (GSK‐3β), and inactivation of GSK‐3â may lead to cardioprotection through suppression of the mitochondrial permeability transition pore (mPTP) opening. The aim of this study was to test if inhibition of phosphodiesterases (PDEs) can moderate the pore opening via GSK‐3β. IBMX (1‐methyl‐3‐isobutylxanthine), a non‐selective inhibitor of PDEs, prevented H2O2‐induced mPTP opening in cardiac cells. IBMX was not able to inhibit the pore opening in cells transfected with the constitutively active GSK‐3β mutant, suggesting that IBMX prevents the pore opening by inactivating GSK‐3β. IBMX reduced reperfusion injury in a GSK‐3β –dependent manner. In support, IBMX significantly increased GSK‐3β phosphorylation at Ser9, an effect that was reversed by both the PKA inhibitor H89 and the PKG inhibitor KT5823, implying that IBMX inactivates GSK‐3β via PKA and PKG. IBMX also activated both PKA and PKG. IBMX failed to prevent the pore opening in cells treated with H89 or PKA siRNA, suggesting a role of PKA in the action of IBMX. Similarly, KT5823 and PKG siRNA also reversed the protective effect of IBMX. In conclusion, inhibition of PDEs prevents the mPTP opening by inactivating GSK‐3β through both PKA and PKG. Inhibition of PDEs may serve a useful approach to attenuate reperfusion injury.