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 3

Increased ox-CaMKII in diabetic patients and mice.

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Increased ox-CaMKII in diabetic patients and mice. (A) Representative im...
(A) Representative immunoblots from right atrial tissues obtained from patients with or without diabetes mellitus and with MI. Band intensity was normalized to Coomassie staining. Summary data show CaMKII (P = 0.7), ox-CaMKII (*P = 0.02), and ox-CaMKII/CaMKII (**P = 0.03) in patients with diabetes mellitus (DM) and MI (n = 5) and MI alone (n = 5). Lanes were run on the same gel but were noncontiguous. (B) Representative immunoblots from right atria tissue obtained from STZ- or vehicle-treated mice. Summary data show CaMKII (P = 0.3), ox-CaMKII (*P = 0.04), and ox-CaMKII/CaMKII (*P = 0.04) in STZ- (n = 5) and vehicle-treated mice (n = 4). Lanes were run on the same gel but were noncontiguous. Band intensity was normalized to Coomassie staining. (C) Representative immunofluorescence images in SAN from mice treated with vehicle or STZ. HCN4 (green) marks SAN, and DAPI (blue) marks nuclei. Scale bars: 50 μm. Summary data show CaMKII (P = 0.8) and ox-CaMKII (**P = 0.005) in STZ- (n = 5) and vehicle-treated mice (n = 3). (D) Ca2+/calmodulin-independent autonomous activity (*P = 0.03, left), full activity (P = 0.08, middle), and autonomous/full activity (**P = 0.01, right) in hearts from STZ- (n = 6) and vehicle-treated mice (n = 4).