期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 3, 页码 1262-1274出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI65268
关键词
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资金
- University of Iowa Cardiovascular Center Interdisciplinary Research Fellowship Training Grant from the NIH
- NIH [R01HL70250, R01HL079031, R01HL113001, R01HL096652]
- Fondation Leducq, Alliance for CaMKII Signaling in Heart [08CVD01]
- Deutsche Forschungsgemeinschaft (DFG)
- Deutsches Zentrum fur Herz-Kreislauf-Forschung (DZHK)
- Fondation Leducq
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 CaMKII delta (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.
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