Diabetes increases mortality after myocardial infarction by oxidizing CaMKII.

Luo M, Guan X, Luczak ED, Lang D, Kutschke W, Gao Z, Yang J, Glynn P, Sossalla S, Swaminathan PD, Weiss RM, Yang B, Rokita AG, Maier LS, Efimov IR, Hund TJ, Anderson ME
J Clin Invest. 2013 123 (3): 1262-74

PMID: 23426181 · PMCID: PMC3673230 · DOI:10.1172/JCI65268

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 CaMKII╬┤ (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.

MeSH Terms (24)

Animals Apoptosis Calcium-Calmodulin-Dependent Protein Kinase Type 2 Cardiac Output Cells, Cultured Diabetes Mellitus, Experimental Female Fibrosis Heart Rate Humans In Vitro Techniques Male Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Mitochondria, Heart Myocardial Infarction Myocardium Oxidation-Reduction Oxidative Stress Peptides Reactive Oxygen Species Sinoatrial Node

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