Abstract 9546: Oxidized Calcium Calmodulin Dependent Kinase II Causes Increased Mortality after Myocardial Infarction in Diabetic Mice

Diabetes increases oxidant stress and doubles the risk of dying suddenly after myocardial infarction (MI) but the mechanisms for increased mortality are unknown. Mice with streptozotocin (STZ)-induced diabetes developed profound heart rate slowing and died at twice the rate of controls after MI surgery. Oxidized CaMKII (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic compared to non-diabetic patients after MI and from STZ-treated diabetic mice. STZ-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by MI. We developed a knock-in mouse model of oxidation-resistant CaMKIIδ (MM-VV). STZ-treated MM-VV mice and wild type mice infused with MitoTEMPOL, a mitochondrial-targeted antioxidant, showed significantly reduced ox-CaMKII, increased pacemaker cell survival, preserved heart rates and were resistant to diabetes attributable mortality after MI. Our findings suggest activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after MI.