Diabetes increases mortality after myocardial infarction by oxidizing CaMKII
Min Luo, … , Thomas J. Hund, Mark E. Anderson
Min Luo, … , Thomas J. Hund, Mark E. Anderson
Published February 15, 2013
Citation Information: J Clin Invest. 2013;123(3):1262-1274. https://doi.org/10.1172/JCI65268.
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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 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.

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

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Figure 6

Mitochondrial ROS increases ox-CaMKII and SAN cell death.

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Mitochondrial ROS increases ox-CaMKII and SAN cell death. (A–C) SAN stai...
(A–C) SAN staining from WT mice treated with STZ alone and MitoTEMPO and STZ and Ncf1–/– mice treated with STZ. DAPI (blue) marks nuclei, HCN4 (green) marks SAN. Scale bars: 50 μm. (A) Representative sections show ox-CaMKII expression. Overall P = 0.006, **P < 0.01 by 1-way ANOVA (n = 3–5 per group). (B) Representative sections show TUNEL-positive cells. Overall P = 0.0006, ***P < 0.01 by 1-way ANOVA (n = 3–7 per group). (C) Fibrosis measured by Masson’s trichrome staining. Overall P = 0.016, *P < 0.05 by 1-way ANOVA (n = 3–4 per group). (D) Proposed model for CaMKII activation by STZ-induced diabetes. STZ-induced hyperglycemia and MI promote mitochondrial ROS generation, which activates ox-CaMKII to cause SND, leading to increased mortality after MI.