Diabetes increases mortality after myocardial infarction by oxidizing CaMKII

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

doi:10.1172/JCI65268

Diabetes increases mortality after myocardial infarction by oxidizing CaMKII

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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160 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1262-1274
Number of pages	13
Journal	Journal of Clinical Investigation
Volume	123
Issue number	3
DOIs	https://doi.org/10.1172/JCI65268
State	Published - Mar 1 2013
Externally published	Yes

ASJC Scopus subject areas

General Medicine

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10.1172/JCI65268

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Luo, M., Guan, X., Luczak, E. D., Lang, D., Kutschke, W., Gao, Z., Yang, J., Glynn, P., Sossalla, S., Swaminathan, P. D., Weiss, R. M., Yang, B., Rokita, A. G., Maier, L. S., Efimov, I. R., Hund, T. J., & Anderson, M. E. (2013). Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. Journal of Clinical Investigation, 123(3), 1262-1274. https://doi.org/10.1172/JCI65268

Luo, M, Guan, X, Luczak, ED, Lang, D, Kutschke, W, Gao, Z, Yang, J, Glynn, P, Sossalla, S, Swaminathan, PD, Weiss, RM, Yang, B, Rokita, AG, Maier, LS, Efimov, IR, Hund, TJ & Anderson, ME 2013, 'Diabetes increases mortality after myocardial infarction by oxidizing CaMKII', Journal of Clinical Investigation, vol. 123, no. 3, pp. 1262-1274. https://doi.org/10.1172/JCI65268

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title = "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.",

author = "Min Luo and Xiaoqun Guan and Luczak, {Elizabeth D.} and Di Lang and William Kutschke and Zhan Gao and Jinying Yang and Patric Glynn and Samuel Sossalla and Swaminathan, {Paari D.} and Weiss, {Robert M.} and Baoli Yang and Rokita, {Adam G.} and Maier, {Lars S.} and Efimov, {Igor R.} and Hund, {Thomas J.} and Anderson, {Mark E.}",

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AU - Luo, Min

AU - Guan, Xiaoqun

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AU - Lang, Di

AU - Kutschke, William

AU - Gao, Zhan

AU - Yang, Jinying

AU - Glynn, Patric

AU - Sossalla, Samuel

AU - Swaminathan, Paari D.

AU - Weiss, Robert M.

AU - Yang, Baoli

AU - Rokita, Adam G.

AU - Maier, Lars S.

AU - Efimov, Igor R.

AU - Hund, Thomas J.

AU - Anderson, Mark E.

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N2 - 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.

AB - 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.

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Diabetes increases mortality after myocardial infarction by oxidizing CaMKII

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