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GSK‐3b inactivation in preventing the myocardium from I/R‐induced injury: Role of eNOS‐derived NO

Inhibition of glycogen synthase kinase (GSK)‐3b has been shown to reduce myocardial cell death following ischemia/reperfusion (I/R). However, the downstream targets of GSK‐3b inactivation are not fully understood. The present study was to investigate the role of endothelial nitric oxide synthase (eNOS) as a downstream target of GSK‐3b inactivation in preventing the myocardium from I/R‐induced injury. Isolated neonatal mouse cardiomyocytes were exposed to anoxia/reoxygenation (A/R; the in vitro counterpart to I/R). Nitric oxide (NO) production and caspase‐3 activity were measured after A/R. Inhibition of GSK‐3b with lithium or SB216763 increased NO production by 3‐fold and reduced A/R‐induced caspase‐3 activation in cardiomyocytes. The effects of lithium or SB216763 on NO production and caspase‐3 activation were absent in eNOS‐/‐ cardiomyocytes. Additionally, a NOS inhibitor, L‐NAME blocked lithium or SB216763‐induced protection after A/R. To investigate the functional significance of GSK‐3b inactivation, isolated mouse hearts were perfused using a Langendorff system. Perfused hearts were subjected to 30 minutes of global ischemia followed by 1 hour of reperfusion. Phosphorylation of eNOS, cardiac apoptosis and myocardial function were assessed after I/R. Lithium treatment during reperfusion increased phosphorylation of eNOS by 4‐fold in the myocardium, reduced cardiac apoptosis and restored myocardial function after global I/R. These protective effects of lithium were not seen in eNOS−/ − hearts. In conclusion, the present studyidentified eNOS‐derived NO as a novel downstream target of GSK‐3beta inactivation in preventing the myocardium from I/R‐induced injury.