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.
View: Text | PDF | Erratum
Research Article Cardiology

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

×

Figure 1

Increased death and SND in WT diabetic mice after MI.

Options: View larger image (or click on image) Download as PowerPoint
Increased death and SND in WT diabetic mice after MI. (A) Survival in WT...
(A) Survival in WT mice treated with vehicle (Veh) (n = 10), STZ (n = 14), STZ and insulin (n = 7), and MitoTEMPO (Mito) and STZ (n = 11) and in AC3-I (n = 13), MM-VV (n = 19), and Ncf1–/– mice treated with STZ (n = 7) after MI. Overall P = 0.005 by 1-way ANOVA, P < 0.05 for comparisons between WT STZ and all other groups except the Ncf1–/– group (P = 0.7). (B–F) In vivo data from ECG-telemetered WT mice treated with vehicle, STZ, STZ and insulin, and MitoTEMPO and STZ and from AC3-I, MM-VV, and Ncf1–/– mice treated with STZ after MI (n = 4–14 per group). (B) Representative heart rate (HR) tracings ending in death. (C) Representative ECGs. Arrowheads indicate P waves. (D) Resting heart rates. Overall P < 0.0001, *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA. (E) Episodes of severe bradycardia (heart rate <200 beats per minute). Overall P = 0.0004, *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA. (F) Spontaneous activity-responsive heart rate (ARHR) increase (overall P = 0.001 for activity 1–10, P = 0.0005 for activity level 11–15, P = 0.0002 for all other activity levels by 1-way ANOVA).