Glycogen synthase kinase 3β together with 14-3-3 protein regulates diabetic cardiomyopathy: Effect of losartan and tempol

Glycogen synthase kinase (GSK) 3β is a multifunctional protein that positively regulates myocardial apoptosis and negatively regulates hypertrophy. However, the role of GSK3β in the diabetic myocardium is largely unknown. We found that GSK3β became more active (less phosphorylated at serine 9) via decreased Akt phosphorylation, in parallel to c-Jun NH2 terminal kinase activation, which correlated with increased activated caspase 3 and myocardial apoptosis 3 days after streptozotocin (STZ) injection in mice. However, 28 days after STZ injection, GSK3β became inactive, which correlated with the enhanced protein kinase C β2 and p38 mitogen activated protein kinase expression, nuclear translocation of nuclear factor of activated T cells c3, cardiac hypertrophy and fibrosis. All of the above parameters were exacerbated in dominant-negative 14-3-3 transgenic mice. Our results suggest that GSK3β together with 14-3-3 protein plays essential roles in the signaling of diabetic cardiomyopathy, and treatment with either losartan or tempol prevents these changes.