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J Clin Invest. 2013 Mar;123(3):1262-74. doi: 10.1172/JCI65268. Epub 2013 Feb 15.

Diabetes increases mortality after myocardial infarction by oxidizing CaMKII.

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  • 1Division of Cardiovascular Medicine, Department of Internal Medicine, Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.

Erratum in

  • J Clin Invest. 2013 May 1;123(5):2333.

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 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.

PMID:
23426181
[PubMed - indexed for MEDLINE]
PMCID:
PMC3673230
Free PMC Article
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