Diabetes increases mortality after myocardial infarction by oxidizing CaMKII

The Journal of clinical investigation (Impact Factor: 13.22). 03/2013; 123(3):1262-74. DOI: 10.1172/JCI65268
Source: PubMed


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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    • "Diabetic patients suffer twice the mortality after MI than do nondiabetic patients, and this is correlated with increased levels of Ca þ þ –calmodulin dependent protein kinase II delta, which is known to be involved in redox control [40]. In an experimental rodent model, the increased mortality associated with diabetes can be eliminated by using a " knock-in " technique rendering this enzyme insensitive to oxidation (it is methionine oxidation which causes the damage) [41]. Also in a rat model of diabetes, the consequences of MI could be drastically reduced by using a cloned thioredoxin-1 gene to express this enzyme to reduce oxidative stress in heart muscle. "
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    ABSTRACT: The overall redox potential of a cell is primarily determined by oxidizable/reducible chemical pairs, including glutathione-glutathione disulfide, reduced thioredoxin-oxidized thioredoxin, and NAD+ − NADH (and NADP-NADPH). Current methods for evaluating oxidative stress rely on detecting levels of individual byproducts of oxidative damage or by determining the total levels or activity of individual antioxidant enzymes. Oxidation-reduction potential (ORP), on the other hand, is an integrated, comprehensive measure of the balance between total (known and unknown) pro-oxidant and antioxidant components in a biological system. Much emphasis has been placed on the role of oxidative stress in chronic diseases, such as Alzheimer’s disease and atherosclerosis. The role of oxidative stress in acute diseases often seen in the emergency room and intensive care unit is considerable. New tools for the rapid, inexpensive measurement of both redox potential and total redox capacity should aid in introducing a new body of literature on the role of oxidative stress in acute illness and how to screen and monitor for potentially beneficial pharmacologic agents.
    01/2015; 257. DOI:10.1016/j.redox.2015.01.006
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    • "Luo and colleagues recently showed that mice with streptozotocin-induced T1DM also develop SAN dysfunction, which manifested as a reduced resting heart rate, prolonged CSNRT and an attenuated chronotropic response to isoprenaline in isolated, perfused hearts [15]. Rats with streptozotocin-induced T1DM also show signs of nodal abnormalities, such as bradycardia and prolongation of the SAN action potential [16,29,30]. "
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    ABSTRACT: Background The aim of this study was to probe cardiac complications, including heart-rate control, in a mouse model of type-2 diabetes. Heart-rate development in diabetic patients is not straight forward: In general, patients with diabetes have faster heart rates compared to non-diabetic individuals, yet diabetic patients are frequently found among patients treated for slow heart rates. Hence, we hypothesized that sinoatrial node (SAN) dysfunction could contribute to our understanding the mechanism behind this conundrum and the consequences thereof.Methods Cardiac hemodynamic and electrophysiological characteristics were investigated in diabetic db/db and control db/+mice.ResultsWe found improved contractile function and impaired filling dynamics of the heart in db/db mice, relative to db/+controls. Electrophysiologically, we observed comparable heart rates in the two mouse groups, but SAN recovery time was prolonged in diabetic mice. Adrenoreceptor stimulation increased heart rate in all mice and elicited cardiac arrhythmias in db/db mice only. The arrhythmias emanated from the SAN and were characterized by large RR fluctuations. Moreover, nerve density was reduced in the SAN region.Conclusions Enhanced systolic function and reduced diastolic function indicates early ventricular remodeling in obese and diabetic mice. They have SAN dysfunction, and adrenoreceptor stimulation triggers cardiac arrhythmia originating in the SAN. Thus, dysfunction of the intrinsic cardiac pacemaker and remodeling of the autonomic nervous system may conspire to increase cardiac mortality in diabetic patients.
    Cardiovascular Diabetology 08/2014; 13(1):122. DOI:10.1186/s12933-014-0122-y · 4.02 Impact Factor
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    • "An additional feature of CaMKII-dependent arrhythmia in heart failure and AF, and probably in acquired disease in general, is the importance of CaMKII-oxidation as a source of kinase hyperactivity (Luczak and Anderson, 2014; see also the review by Erickson, 2014 in this special issue). This mode of CaMKII activation appears to be particularly important in sinus node (SN) dysfunction accompanying heart failure (Swaminathan et al., 2011), in AF (Purohit et al., 2013), and diabetic cardiomyopathy (Luo et al., 2013). Finally, one of the most important roles that CaMKII plays in acquired disease is as a controller of the expression of several key ion channels and transporters, and many disease-associated changes in expression of these proteins appear to require CaMKII. "
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    ABSTRACT: Calcium/calmodulin-dependent protein kinase II (CaMKII) activity has been shown to contribute to arrhythmogenesis in a remarkably broad range of cardiac pathologies. Several of these involve significant structural and electrophysiologic remodeling, whereas others are due to specific channelopathies, and are not typically associated with arrhythmogenic changes to protein expression or cellular and tissue structure. The ability of CaMKII to contribute to arrhythmia across such a broad range of phenotypes suggests one of two interpretations regarding the role of CaMKII in cardiac arrhythmia: (1) some CaMKII-dependent mechanism is a common driver of arrhythmia irrespective of the specific etiology of the disease, or (2) these different etiologies expose different mechanisms by which CaMKII is capable of promoting arrhythmia. In this review, we dissect the available mechanistic evidence to explore these two possibilities and discuss how the various molecular actions of CaMKII promote arrhythmia in different pathophysiologic contexts.
    Frontiers in Pharmacology 05/2014; 5:110. DOI:10.3389/fphar.2014.00110 · 3.80 Impact Factor
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