Diabetes doubled mortality and increased ox-CaMKII in pacemaker tissues after myocardial infarction, while oxidation-resistant CaMKIIδ or mitochondrial antioxidants prevented this mortality in mice.
Does inhibition of ox-CaMKII via MitoTEMPO or genetic mutation prevent diabetes-attributable mortality and heart rate slowing after myocardial infarction in mice?
Activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction, and its inhibition prevents mortality in diabetic mice.
Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca(2+)/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction.
Luo et al. (Fri,) conducted a other in Myocardial infarction and diabetes. Diabetes vs. Nondiabetic controls was evaluated on Mortality after myocardial infarction. Diabetes doubled mortality and increased ox-CaMKII in pacemaker tissues after myocardial infarction, while oxidation-resistant CaMKIIδ or mitochondrial antioxidants prevented this mortality in mice.