Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis

Spindler, Matthias; Meyer, Klas; Strömer, Hinrik; Leupold, Andrea; Boehm, Ernest; Wagner, H.; Neubauer, Stefan

doi:10.1152/ajpheart.01016.2003

Cited by 63 publications

(52 citation statements)

References 27 publications

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“…Therapies to improve vascular supply and myocardial perfusion in remote zones of remodeling myocardium may thus provide a strategy to attenuate the remodeling process. CK Ϫ/Ϫ mice were previously reported to have increased susceptibility to ischemic injury in the setting of the isolated perfused heart model (19). On the other hand, LV dilatation after MI is not aggravated in CK Ϫ/Ϫ mice (15), and we found a similar decline in myocardial perfusion (Fig.…”

Section: Discussionsupporting

confidence: 78%

Multimodal functional cardiac MRI in creatine kinase-deficient mice reveals subtle abnormalities in myocardial perfusion and mechanics

Nahrendorf

Streif²,

Hiller³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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, and Wolfgang R. Bauer. Multimodal functional cardiac MRI in creatine kinasedeficient mice reveals subtle abnormalities in myocardial perfusion and mechanics. Am J Physiol Heart Circ Physiol 290: H2516-H2521, 2006. First published January 13, 2006; doi:10.1152/ajpheart.01038.2005.-A decrease in the supply of ATP from the creatine kinase (CK) system is thought to contribute to the evolution of heart failure. However, previous studies on mice with a combined knockout of the mitochondrial and cytosolic CK (CK Ϫ/Ϫ ) have not revealed overt left ventricular dysfunction. The aim of this study was to employ novel MRI techniques to measure maximal myocardial velocity (Vmax) and myocardial perfusion and thus determine whether abnormalities in the myocardial phenotype existed in CK Ϫ/Ϫ mice, both at baseline and 4 wk after myocardial infarction (MI Ϫ/Ϫ MI, 3.71 Ϯ 0.57 ml/g ⅐ min, P ϭ NS, P Ͻ 0.05 vs. baseline), paralleled by a significantly reduced capillary density (histology). In conclusion, myocardial function in transgenic mice may appear normal when only gross indexes of performance such as EF are assessed. However, the use of a combination of novel MRI techniques to measure myocardial perfusion and mechanics allowed the abnormalities in the CK Ϫ/Ϫ phenotype to be detected. The myocardium in CK-deficient mice is characterized by reduced perfusion and reduced maximal contraction velocity, suggesting that the myocardial hypertrophy seen in these mice cannot fully compensate for the absence of the CK system. magnetic resonance imaging; contractility; myocardial infarction CHANGES IN myocardial energetics, including reduced levels of phosphocreatine, creatine kinase (CK) (10, 16), and ATP (20), have been documented in the failing heart. However, whether these alterations in myocardial energetics are a causal mechanism contributing to left ventricular (LV) remodeling and dysfunction or an adaptive phenomenon has yet to be resolved. Recently, our group reported that deletion of the CK enzyme system [double knockout of the mitochondrial and cytosolic CK (CK Ϫ/Ϫ )] leads to adaptive changes of the murine heart, consisting of LV hypertrophy and mild dilatation of the LV. However, cardiac output and LV ejection fraction remained normal in these mice (15). Furthermore, when CK Ϫ/Ϫ mice were examined 4 wk after the induction of myocardial infarction (MI), no evidence of adverse LV remodeling was seen (15). Therefore, the aim of the current study was to determine whether the use of novel techniques in mouse cardiac MRI, such as perfusion imaging and the imaging of myocardial mechanics, would allow subtle abnormalities of the myocardial phenotype to be detected.A phase-contrast MRI pulse sequence, recently developed by our group (21) to measure myocardial contraction velocity and mechanics in mice, was used in this study. In addition, a second novel MR technique to quantify myocardial perfusion, which has also recently been modified to work in the small and rapidly beating mouse heart (12, 22), was employed to assess myocardial p...

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Section: Discussionsupporting

confidence: 78%

Multimodal functional cardiac MRI in creatine kinase-deficient mice reveals subtle abnormalities in myocardial perfusion and mechanics

Nahrendorf

Streif²,

Hiller³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…It has been shown that NCX activity is altered during cardiac remodeling in the hypertrophic heart and during heart failure (7,41). The hearts from CKM and sMiCK double knock-out mice have been demonstrated to show increased sensitivity to ischemia- reperfusion injury and show a greater increase in diastolic Ca 2ϩ concentration during ischemia (42); therefore the interaction between NCX1 and CKs may be important to prolonging normal heart functioning when a pathological condition such as ischemia starts to develop. In sMiCK knock-out mice, there are no obvious change in the morphology and functioning of the muscles (43).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Sodium-Calcium Exchanger Activity by Creatine Kinase under Energy-compromised Conditions

Yang¹,

Fann²,

Chang³

et al. 2010

Journal of Biological Chemistry

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Na؉ /Ca 2؉ exchanger (NCX) is one of the major mechanisms for removing Ca 2؉ from the cytosol especially in cardiac myocytes and neurons, where their physiological activities are triggered by an influx of Ca 2؉ . NCX contains a large intracellular loop (NCXIL) that is responsible for regulating NCX activity. Recent evidence has shown that proteins, including kinases and phosphatases, associate with NCX1IL to form a NCX1 macromolecular complex. To search for the molecules that interact with NCX1IL and regulate NCX1 activity, we used the yeast twohybrid method to screen a human heart cDNA library and found that the C-terminal region of sarcomeric mitochondrial creatine kinase (sMiCK) interacted with NCX1IL. Moreover, both sMiCK and the muscle-type creatine kinase (CKM) coimmunoprecipitated with NCX1 using lysates of cardiacmyocytes and HEK293T cells that transiently expressed NCX1 and various creatine kinases. Both sMiCK and CKM were able to produce a recovery in the decreased NCX1 activity that was lost under energy-compromised conditions. This regulation is mediated through a putative PKC phosphorylation site of sMiCK and CKM. The autophosphorylation and the catalytic activity of sMiCK and CKM are not required for their regulation of NCX1 activity. Our results suggest a novel mechanism for the regulation of NCX1 activity.

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Section: Perspective 2: Cardiovascular Metabolism As a Physical Spatmentioning

confidence: 99%

“…Genetically engineered mice lacking mitochondrial and cytosolic CK had nearly normal cardiac performance, up to at least moderate workloads (44)(45)(46). However, they showed increased susceptibility to ischemic injury (46) and electrical instability during stress (47) as well as a markedly reduced work capacity during voluntary exercise (48). Mice with undetectable levels of creatine phosphate attributable to knock out of a critical enzyme required for creatine synthesis also had normal resting cardiac function but a markedly impaired inotropic reserve in response to adrenergic stimulation (49).…”

Section: Perspective 2: Cardiovascular Metabolism As a Physical Spatmentioning

confidence: 99%

Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Network perspectives of cardiovascular metabolism

Weiss

Yang

2006

Journal of Lipid Research

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In this review, we examine cardiovascular metabolism from three different, but highly complementary, perspectives. First, from the abstract perspective of a metabolite network, composed of nodes and links. We present fundamental concepts in network theory, including emergence, to illustrate how nature has designed metabolism with a hierarchal modular scale-free topology to provide a robust system of energy delivery. Second, from the physical perspective of a modular spatially compartmentalized network. We review evidence that cardiovascular metabolism is functionally compartmentalized, such that oxidative phosphorylation, glycolysis, and glycogenolysis preferentially channel ATP to ATPases in different cellular compartments, using creatine kinase and adenylate kinase to maximize efficient energy delivery. Third, from the dynamics perspective, as a network of dynamically interactive metabolic modules capable of self-oscillation. Whereas normally, cardiac metabolism exists in a regime in which excitation-metabolism coupling closely matches energy supply and demand, we describe how under stressful conditions, the network can be pushed into a qualitatively new dynamic regime, manifested as cell-wide oscillations in ATP levels, in which the coordination between energy supply and demand is lost. We speculate how this state of "metabolic fibrillation" leads to cell death if not corrected and discuss the implications for cardioprotection.-Weiss, J. N., L. Yang, and Z. Qu. Network perspectives of cardiovascular metabolism. J. Lipid Res. 2006Res. . 47: 2355Res. -2366. Supplementary key words mitochondriaMuscle cells must adapt rapidly to a much wider range of energy demands than most noncontractile cells. For example, the rate of respiration by cardiac muscle increases by a factor of 15-20 between unloaded and maximal workload conditions (1). This requires a very robust metabolic network that can deliver smooth performance over a wide range of parameters. Although we do not yet fully understand how this is accomplished, new systems biology approaches, complemented by network theory and computer modeling studies, are at the threshold of providing new insights.Cardiovascular metabolism can be viewed as a network of interlinked energy-produced pathways (e.g., oxidative phosphorylation, glycolysis, and glycogenolysis), energyconsuming pathways [e.g., myofilament, sarcoplasmic reticulum (SR), and sarcolemma (SL) ATPases], and energydistributing pathways [e.g., creatine kinase (CK) and adenylate kinase (AK)] (Fig. 1A). In this review, we begin by considering metabolism from a highly abstract perspective, as a metabolite network in which substrates/products are represented as nodes and metabolic enzymes are represented as the links between nodes. We present some fundamental concepts in network theory, including the concept of emergence, and discuss how through Darwinian evolution metabolic networks are likely to have evolved a scale-free hierarchal modular topology that ensures the robustness of this most fundamental ...

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Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis

Cited by 63 publications

References 27 publications

Multimodal functional cardiac MRI in creatine kinase-deficient mice reveals subtle abnormalities in myocardial perfusion and mechanics

Multimodal functional cardiac MRI in creatine kinase-deficient mice reveals subtle abnormalities in myocardial perfusion and mechanics

Regulation of Sodium-Calcium Exchanger Activity by Creatine Kinase under Energy-compromised Conditions

Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Network perspectives of cardiovascular metabolism

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