Diabetes increases mortality after myocardial infarction by oxidizing CaMKII.

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.

• Authors: Min Luo, Xiaoqun Guan, Elizabeth D Luczak, Di Lang, William Kutschke, Zhan Gao, Jinying Yang, Patric Glynn, Samuel Sossalla, Paari D Swaminathan, Robert M Weiss, Baoli Yang, Adam G Rokita, Lars S Maier, Igor R Efimov, Thomas J Hund, Mark E Anderson
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 3 Pg. 1262-74 (Mar 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 23426181 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AC3-I peptide
• Peptides
• Reactive Oxygen Species
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Animals
• Apoptosis
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics, metabolism)
• Cardiac Output
• Cells, Cultured
• Diabetes Mellitus, Experimental (complications, enzymology, mortality)
• Female
• Fibrosis
• Heart Rate
• Humans
• In Vitro Techniques
• Male
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria, Heart (metabolism)
• Myocardial Infarction (enzymology, etiology, mortality)
• Myocardium (enzymology, pathology)
• Oxidation-Reduction
• Oxidative Stress
• Peptides (pharmacology)
• Reactive Oxygen Species (metabolism)
• Sinoatrial Node (enzymology, pathology, physiopathology)