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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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

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Figure 5

SAN cell death and fibrosis lead to decreased conduction velocity and spontaneous beating.

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SAN cell death and fibrosis lead to decreased conduction velocity and sp...
(A) Cell loss data from vehicle- and STZ-treated WT mice were incorporated into a 2-dimensional histologically reconstructed mathematical model of the intact sinoatrial node (action potentials from central [Cen] and peripheral [Per] SAN and right atrium are shown). The STZ model with 19% cell loss in the SAN predicts a shift of lead pacemaker site (red asterisks on action potential traces), slowing of conduction time and block (double red lines on action potential traces), and decreased heart rate similar to experimental measurements. Red arrows denote direction of action potential propagation. (B) Mouse atria prepared for optical measurements (left). Original magnification, ×20. Representative pseudocolored isochrones from optical mapping (middle and right). SVC, superior vena cava; AVN, atrioventricular node; IVC, inferior vena cava; LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; CT, crista terminalis. White asterisks denote the earliest activation in the SAN. (C) Conduction velocity during pacing in STZ- and vehicle-treated mice in the absence (**P = 0.004; n = 5 per group) and presence of isoproterenol (3 nM, *P = 0.01; n = 5 per group). (D) Heart rate in isolated atria in the absence (*P = 0.03; n = 4–5 per group) or presence of isoproterenol (ISO; 3 nM, **P = 0.0056; n = 4–5 per group).