Diabetes increases mortality after myocardial infarction by oxidizing CaMKII
Open Access
- 15 February 2013
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (3), 1262-1274
- https://doi.org/10.1172/jci65268
Abstract
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 Ca2+/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.Keywords
This publication has 76 references indexed in Scilit:
- CaMKII determines mitochondrial stress responses in heartNature, 2012
- Calcium Signaling through CaMKII Regulates Hepatic Glucose Production in Fasting and ObesityCell Metabolism, 2012
- Oxidation of CaMKII determines the cardiotoxic effects of aldosteroneNature Medicine, 2011
- CaMKII in the Cardiovascular System: Sensing Redox StatesPhysiological Reviews, 2011
- Therapeutic Targeting of Mitochondrial Superoxide in HypertensionCirculation Research, 2010
- Effects of tempol and redox-cycling nitroxides in models of oxidative stressPharmacology & Therapeutics, 2010
- Calmodulin kinase II is required for fight or flight sinoatrial node physiologyProceedings of the National Academy of Sciences of the United States of America, 2009
- The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overloadProceedings of the National Academy of Sciences of the United States of America, 2009
- Effects of Intensive Glucose Lowering in Type 2 DiabetesNew England Journal of Medicine, 2008
- A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine OxidationCell, 2008