Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse.

Abstract

The inactivation of glycogen synthase kinase-3beta (GSK-3beta) is proposed as the event integrating protective pathways initiated by preconditioning and other interventions. The inactivation of GSK-3 is thought to decrease the probability of opening of the mitochondrial permeability transition pore. The aim of this study was to verify the role of GSK-3 using a targeted mouse line lacking the critical N-terminal serine within GSK-3beta (Ser9) and the highly homologous GSK-3alpha (Ser21), which when phosphorylated results in kinase inactivation. Postconditioning with 10 cycles of 5 seconds of reperfusion/5 seconds of ischemia and preconditioning with 6 cycles of 4 minutes of ischemia/6 minutes of reperfusion, similarly reduced infarction of the isolated perfused mouse heart in response to 30 minutes of global ischemia and 120 minutes of reperfusion. Preconditioning caused noticeable inactivating phosphorylation of GSK-3. However, both preconditioning and postconditioning still protected hearts of homozygous GSK-3 double knockin mice. Moreover, direct pharmacological inhibition of GSK-3 catalytic activity with structurally diverse inhibitors before or after ischemia failed to recapitulate conditioning protection. Nonetheless, cyclosporin A, a direct mitochondrial permeability transition pore inhibitor, reduced infarction in hearts from both wild-type and homozygous GSK-3 double knockin mice. Furthermore, in adult cardiac myocytes from GSK-3 double knockin mice, insulin exposure was still as effective as cyclosporin A in delaying mitochondrial permeability transition pore opening. Our results, which include a novel genetic approach, suggest that the inhibition of GSK-3 is unlikely to be the key determinant of cardioprotective signaling in either preconditioning or postconditioning in the mouse.

• Authors: Yasuhiro Nishino, Ian G Webb, Sean M Davidson, Aminul I Ahmed, James E Clark, Sebastien Jacquet, Ajay M Shah, Tetsuji Miura, Derek M Yellon, Metin Avkiran, Michael S Marber
• Journal: Circulation research (Circ Res) Vol. 103 Issue 3 Pg. 307-14 (Aug 01 2008) ISSN: 1524-4571 [Electronic] United States
• PMID: 18583716 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Enzyme Inhibitors
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Cyclosporine
• Glycogen Synthase Kinase 3
• glycogen synthase kinase 3 alpha

Topics

• Animals
• Cardiotonic Agents
• Cyclosporine (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Glycogen Synthase Kinase 3 (genetics, metabolism, physiology)
• Ischemic Preconditioning, Myocardial (methods)
• Mice
• Mice, Transgenic
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Myocardial Infarction (prevention & control)
• Myocardial Reperfusion Injury (drug therapy)
• Phosphorylation