48 results on '"Zuurbier, C.J."'
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2. Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?
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Nikolaou, P.E. Mylonas, N. Makridakis, M. Makrecka-Kuka, M. Iliou, A. Zerikiotis, S. Efentakis, P. Kampoukos, S. Kostomitsopoulos, N. Vilskersts, R. Ikonomidis, I. Lambadiari, V. Zuurbier, C.J. Latosinska, A. Vlahou, A. Dimitriadis, G. Iliodromitis, E.K. Andreadou, I. more...
- Abstract
Major clinical trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) exhibit protective effects against heart failure events, whereas inconsistencies regarding the cardiovascular death outcomes are observed. Therefore, we aimed to compare the selective SGLT-2i empagliflozin (EMPA), dapagliflozin (DAPA) and ertugliflozin (ERTU) in terms of infarct size (IS) reduction and to reveal the cardioprotective mechanism in healthy non-diabetic mice. C57BL/6 mice randomly received vehicle, EMPA (10 mg/kg/day) and DAPA or ERTU orally at the stoichiometrically equivalent dose (SED) for 7 days. 24 h-glucose urinary excretion was determined to verify SGLT-2 inhibition. IS of the region at risk was measured after 30 min ischemia (I), and 120 min reperfusion (R). In a second series, the ischemic myocardium was collected (10th min of R) for shotgun proteomics and evaluation of the cardioprotective signaling. In a third series, we evaluated the oxidative phosphorylation capacity (OXPHOS) and the mitochondrial fatty acid oxidation capacity by measuring the respiratory rates. Finally, Stattic, the STAT-3 inhibitor and wortmannin were administered in both EMPA and DAPA groups to establish causal relationships in the mechanism of protection. EMPA, DAPA and ERTU at the SED led to similar SGLT-2 inhibition as inferred by the significant increase in glucose excretion. EMPA and DAPA but not ERTU reduced IS. EMPA preserved mitochondrial functionality in complex I&II linked oxidative phosphorylation. EMPA and DAPA treatment led to NF-kB, RISK, STAT-3 activation and the downstream apoptosis reduction coinciding with IS reduction. Stattic and wortmannin attenuated the cardioprotection afforded by EMPA and DAPA. Among several upstream mediators, fibroblast growth factor-2 (FGF-2) and caveolin-3 were increased by EMPA and DAPA treatment. ERTU reduced IS only when given at the double dose of the SED (20 mg/kg/day). Short-term EMPA and DAPA, but not ERTU administration at the SED reduce IS in healthy non-diabetic mice. Cardioprotection is not correlated to SGLT-2 inhibition, is STAT-3 and PI3K dependent and associated with increased FGF-2 and Cav-3 expression. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany. more...
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- 2022
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3. Empagliflozin reduces TNFa-induced reactive oxygen species through inhibition of the human endothelial Na+/H+ exchanger 1
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Uthman, L, primary, Baumgart, P, additional, Baartscheer, A, additional, Schumacher, C.A, additional, Li, X, additional, Hermanides, J, additional, Preckel, B, additional, Hollmann, M.W, additional, Coronel, R.C, additional, Zuurbier, C.J, additional, and Weber, N.C, additional more...
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- 2021
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4. Perioperative hyperinsulinaemic normoglycaemic clamp causes hypolipidaemia after coronary artery surgery
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Zuurbier, C.J., Hoek, F.J., van Dijk, J., Abeling, N.G., Meijers, J.C.M., Levels, J.H.M., de Jonge, E., de Mol, B.A., and Van Wezel, H.B.
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- 2008
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5. Chronic Empagliflozin Treatment Reduces Myocardial Infarct Size in Nondiabetic Mice through STAT-3-Mediated Protection on Microvascular Endothelial Cells and Reduction of Oxidative Stress
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Nikolaou, P.E. Efentakis, P. Abu Qourah, F. Femminò, S. Makridakis, M. Kanaki, Z. Varela, A. Tsoumani, M. Davos, C.H. Dimitriou, C.A. Tasouli, A. Dimitriadis, G. Kostomitsopoulos, N. Zuurbier, C.J. Vlahou, A. Klinakis, A. Brizzi, M.F. Iliodromitis, E.K. Andreadou, I. more...
- Abstract
Aims: Empagliflozin (EMPA) demonstrates cardioprotective effects on diabetic myocardium but its infarct-sparing effects in normoglycemia remain unspecified. We investigated the acute and chronic effect of EMPA on infarct size after ischemia-reperfusion (I/R) injury and the mechanisms of cardioprotection in nondiabetic mice. Results: Chronic oral administration of EMPA (6 weeks) reduced myocardial infarct size after 30 min/2 h I/R (26.5% ± 3.9% vs 45.8% ± 3.3% in the control group, p < 0.01). Body weight, blood pressure, glucose levels, and cardiac function remained unchanged between groups. Acute administration of EMPA 24 or 4 h before I/R did not affect infarct size. Chronic EMPA treatment led to a significant reduction of oxidative stress biomarkers. STAT-3 (signal transducer and activator of transcription 3) was activated by Y(705) phosphorylation at the 10th minute of R, but it remained unchanged at 2 h of R and in the acute administration protocols. Proteomic analysis was employed to investigate signaling intermediates and revealed that chronic EMPA treatment regulates several pathways at reperfusion, including oxidative stress and integrin-related proteins that were further evaluated. Superoxide dismutase and vascular endothelial growth factor were increased throughout reperfusion. EMPA pretreatment (24 h) increased the viability of human microvascular endothelial cells in normoxia and on 3 h hypoxia/1 h reoxygenation and reduced reactive oxygen species production. In EMPA-treated murine hearts, CD31-/VEGFR2-positive endothelial cells and the pSTAT-3(Y705) signal derived from endothelial cells were boosted at early reperfusion. Innovation: Chronic EMPA administration reduces infarct size in healthy mice via the STAT-3 pathway and increases the survival of endothelial cells. Conclusion: Chronic but not acute administration of EMPA reduces infarct size through STAT-3 activation independently of diabetes mellitus. © Copyright 2021, Mary Ann Liebert, Inc., publishers 2021. more...
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- 2021
6. Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signaling
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Andreadou, I. Daiber, A. Baxter, G.F. Brizzi, M.F. Di Lisa, F. Kaludercic, N. Lazou, A. Varga, Z.V. Zuurbier, C.J. Schulz, R. Ferdinandy, P.
- Abstract
The morbidity and mortality from cardiovascular diseases (CVD) remain high. Metabolic diseases such as obesity, hyperlipidemia, diabetes mellitus (DM), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as well as hypertension are the most common comorbidities in patients with CVD. These comorbidities result in increased myocardial oxidative stress, mainly from increased activity of nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, mitochondria as well as downregulation of antioxidant defense systems. Oxidative and nitrosative stress play an important role in ischemia/reperfusion injury and may account for increased susceptibility of the myocardium to infarction and myocardial dysfunction in the presence of the comorbidities. Thus, while early reperfusion represents the most favorable therapeutic strategy to prevent ischemia/reperfusion injury, redox therapeutic strategies may provide additive benefits, especially in patients with heart failure. While oxidative and nitrosative stress are harmful, controlled release of reactive oxygen species is however important for cardioprotective signaling. In this review we summarize the current data on the effect of hypertension and major cardiometabolic comorbidities such as obesity, hyperlipidemia, DM, NAFLD/NASH on cardiac redox homeostasis as well as on ischemia/reperfusion injury and cardioprotection. We also review and discuss the therapeutic interventions that may restore the redox imbalance in the diseased myocardium in the presence of these comorbidities. © 2021 Elsevier Inc. more...
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- 2021
7. The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury
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Xiao, Y., Yim, K., Zhang, H, Bakker, D. de, Nederlof, R., Smeitink, J.A.M., Renkema, H., Hollmann, M.W., Weber, N.C., Zuurbier, C.J., Xiao, Y., Yim, K., Zhang, H, Bakker, D. de, Nederlof, R., Smeitink, J.A.M., Renkema, H., Hollmann, M.W., Weber, N.C., and Zuurbier, C.J. more...
- Abstract
Item does not contain fulltext, PURPOSE: Sonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m's potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia. METHODS: Isolated C56Bl/6N mouse hearts were Langendorff-perfused and subjected to short (20 min) or long (30 min) ischemia, followed by reperfusion. During perfusion, hearts were treated with saline, 10 μM KH176m, or 1 mM MPG. Cardiac function, cell death (necrosis), and mitochondrial damage (cytochrome c (CytC) release) were evaluated. In additional series, the effect of KH176m treatment on the irreversible oxidative stress marker 4-hydroxy-2-nonenal (4-HNE), formed during ischemia only, was determined at 30-min reperfusion. RESULTS: During baseline conditions, both drugs reduced cardiac performance, with opposing effects on vascular resistance (increased with KH176m, decreased with MPG). For short ischemia, KH176m robustly reduced all cell death parameters: LDH release (0.2 ± 0.2 vs 0.8 ± 0.5 U/min/GWW), infarct size (15 ± 8 vs 31 ± 20%), and CytC release (168.0 ± 151.9 vs 790.8 ± 453.6 ng/min/GWW). Protection by KH176m was associated with decreased cardiac 4-HNE. MPG only reduced CytC release. Following long ischemia, IRI was doubled, and KH176m and MPG now only reduced LDH release. The reduced protection against long ischemia was associated with the inability to reduce cardiac 4-HNE. CONCLUSION: Protection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, ir more...
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- 2021
8. IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria: guidelines of the EU-CARDIOPROTECTION COST Action
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Lecour, S., Andreadou, I., Bøtker, H.E., Davidson, S.M., Heusch, G., Ruiz-Meana, M., Schulz, R., Zuurbier, C.J., Royen, N. van, Ferdinandy, P., Hausenloy, D.J., Lecour, S., Andreadou, I., Bøtker, H.E., Davidson, S.M., Heusch, G., Ruiz-Meana, M., Schulz, R., Zuurbier, C.J., Royen, N. van, Ferdinandy, P., and Hausenloy, D.J. more...
- Abstract
Contains fulltext : 239037.pdf (Publisher’s version ) (Open Access), Acute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies ('IMPACT'), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit. more...
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- 2021
9. Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.
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Bakermans, A.J., Boekholdt, S.Matthijs, Vries, D.K. de, Reckman, Y.J., Farag, E.S., Heer, P. de, Uthman, L., Denis, S.W., Zuurbier, C.J., Houtkooper, R.H., Koolbergen, D.R., Kluin, J., Planken, R.N., Lamb, H.J., Webb, A.G., Strijkers, G.J., Beard, D.A., Jeneson, J.A.L., Nederveen, A.J., Bakermans, A.J., Boekholdt, S.Matthijs, Vries, D.K. de, Reckman, Y.J., Farag, E.S., Heer, P. de, Uthman, L., Denis, S.W., Zuurbier, C.J., Houtkooper, R.H., Koolbergen, D.R., Kluin, J., Planken, R.N., Lamb, H.J., Webb, A.G., Strijkers, G.J., Beard, D.A., Jeneson, J.A.L., and Nederveen, A.J. more...
- Abstract
01 augustus 2021, Item does not contain fulltext, BACKGROUND: Proton magnetic resonance spectroscopy ((1) H-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking. PURPOSE: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized (1) H-MRS. STUDY TYPE: Test-retest repeatability and measurement validation study. SUBJECTS: Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy. FIELD STRENGTH/SEQUENCE: Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T. ASSESSMENT: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the (1) H-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo (1) H-MRS measurements against biochemical assays in myocardial tissue from the same subjects. STATISTICAL TESTS: Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between (1) H-MRS measurements and biochemical assay was tested with regression analyses. RESULTS: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with (1) H-MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05. DATA CONCLUSION: We validated the use of localized (1) H-MRS of the human heart at 3 T for quantitati more...
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- 2021
10. Mechanical ventilation of mice
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Schwarte, L.A., Zuurbier, C.J., and Ince, C.
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- 2000
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11. The dynamic regulation of myocardial oxidative phosphorylation: Analysis of the response time of oxygen consumption
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van Beek, J.H.G.M., Tian, X., Zuurbier, C.J., de Groot, B., van Echteld, C.J.A., Eijgelshoven, M.H.J., and Hak, J.B.
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- 1998
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12. Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: effects on inflammatory response during coronary artery surgery
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Visser, L., Zuurbier, C.J., Hoek, F.J., Opmeer, B.C., de Jonge, E., de Mol, B.A.J.M., and van Wezel, H.B.
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- 2005
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13. Effect of hyperglycaemia and diabetes on acute myocardial ischaemia–reperfusion injury and cardioprotection by ischaemic conditioning protocols
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Penna, C. Andreadou, I. Aragno, M. Beauloye, C. Bertrand, L. Lazou, A. Falcão-Pires, I. Bell, R. Zuurbier, C.J. Pagliaro, P. Hausenloy, D.J.
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cardiovascular diseases - Abstract
Diabetic patients are at increased risk of developing coronary artery disease and experience worse clinical outcomes following acute myocardial infarction. Novel therapeutic strategies are required to protect the myocardium against the effects of acute ischaemia–reperfusion injury (IRI). These include one or more brief cycles of non-lethal ischaemia and reperfusion prior to the ischaemic event (ischaemic preconditioning [IPC]) or at the onset of reperfusion (ischaemic postconditioning [IPost]) either to the heart or to extracardiac organs (remote ischaemic conditioning [RIC]). Studies suggest that the diabetic heart is resistant to cardioprotective strategies, although clinical evidence is lacking. We overview the available animal models of diabetes, investigating acute myocardial IRI and cardioprotection, experiments investigating the effects of hyperglycaemia on susceptibility to acute myocardial IRI, the response of the diabetic heart to cardioprotective strategies e.g. IPC, IPost and RIC. Finally we highlight the effects of anti-hyperglycaemic agents on susceptibility to acute myocardial IRI and cardioprotection. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc. © 2020 The British Pharmacological Society more...
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- 2020
14. SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models
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Andreadou, I. Bell, R.M. Bøtker, H.E. Zuurbier, C.J.
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The sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of effective drugs managing patients, who suffer from type 2 diabetes (T2D): Landmark clinical trials including EMPA-REG, CANVAS and Declare-TIMI have demonstrated that SGLT2 inhibitors reduce cardiovascular mortality and re-hospitalization for heart failure (HF) in patients with T2D. It is well established that there is a strong independent relationship among infarct size measured within 1 month after reperfusion and all-cause death and hospitalization for HF: The fact that cardiovascular mortality was significantly reduced with the SGLT2 inhibitors, fuels the assumption that this class of therapies may attenuate myocardial infarct size. Experimental evidence demonstrates that SGLT2 inhibitors exert cardioprotective effects in animal models of acute myocardial infarction through improved function during the ischemic episode, reduction of infarct size and a subsequent attenuation of heart failure development. The aim of the present review is to outline the current state of preclinical research in terms of myocardial ischemia/reperfusion injury (I/R) and infarct size for clinically available SGLT2 inhibitors and summarize some of the proposed mechanisms of action (lowering intracellular Na+ and Ca2+, NHE inhibition, STAT3 and AMPK activation, CamKII inhibition, reduced inflammation and oxidative stress) that may contribute to the unexpected beneficial cardiovascular effects of this class of compounds. © 2020 Elsevier B.V. more...
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- 2020
15. Cardiac metabolism as a driver and therapeutic target of myocardial infarction
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Zuurbier, C.J. Bertrand, L. Beauloye, C.R. Andreadou, I. Ruiz-Meana, M. Jespersen, N.R. Kula-Alwar, D. Prag, H.A. Eric Botker, H. Dambrova, M. Montessuit, C. Kaambre, T. Liepinsh, E. Brookes, P.S. Krieg, T. more...
- Abstract
Reducing infarct size during a cardiac ischaemic-reperfusion episode is still of paramount importance, because the extension of myocardial necrosis is an important risk factor for developing heart failure. Cardiac ischaemia-reperfusion injury (IRI) is in principle a metabolic pathology as it is caused by abruptly halted metabolism during the ischaemic episode and exacerbated by sudden restart of specific metabolic pathways at reperfusion. It should therefore not come as a surprise that therapy directed at metabolic pathways can modulate IRI. Here, we summarize the current knowledge of important metabolic pathways as therapeutic targets to combat cardiac IRI. Activating metabolic pathways such as glycolysis (eg AMPK activators), glucose oxidation (activating pyruvate dehydrogenase complex), ketone oxidation (increasing ketone plasma levels), hexosamine biosynthesis pathway (O-GlcNAcylation; administration of glucosamine/glutamine) and deacetylation (activating sirtuins 1 or 3; administration of NAD+-boosting compounds) all seem to hold promise to reduce acute IRI. In contrast, some metabolic pathways may offer protection through diminished activity. These pathways comprise the malate-aspartate shuttle (in need of novel specific reversible inhibitors), mitochondrial oxygen consumption, fatty acid oxidation (CD36 inhibitors, malonyl-CoA decarboxylase inhibitors) and mitochondrial succinate metabolism (malonate). Additionally, protecting the cristae structure of the mitochondria during IR, by maintaining the association of hexokinase II or creatine kinase with mitochondria, or inhibiting destabilization of FOF1-ATPase dimers, prevents mitochondrial damage and thereby reduces cardiac IRI. Currently, the most promising and druggable metabolic therapy against cardiac IRI seems to be the singular or combined targeting of glycolysis, O-GlcNAcylation and metabolism of ketones, fatty acids and succinate. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd more...
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- 2020
16. In vivo mouse myocardial (31)P MRS using three-dimensional image-selected in vivo spectroscopy (3D ISIS): technical considerations and biochemical validations
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Bakermans, A.J., Abdurrachim, D., Nierop, B.J. van, Koeman, A., Kroon, I. van der, Baartscheer, A., Schumacher, C.A., Strijkers, G.J., Houten, S.M., Zuurbier, C.J., Nicolay, K., and Prompers, J.J.
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Other Research Radboud Institute for Health Sciences [Radboudumc 0] - Abstract
Item does not contain fulltext (31)P MRS provides a unique non-invasive window into myocardial energy homeostasis. Mouse models of cardiac disease are widely used in preclinical studies, but the application of (31)P MRS in the in vivo mouse heart has been limited. The small-sized, fast-beating mouse heart imposes challenges regarding localized signal acquisition devoid of contamination with signal originating from surrounding tissues. Here, we report the implementation and validation of three-dimensional image-selected in vivo spectroscopy (3D ISIS) for localized (31)P MRS of the in vivo mouse heart at 9.4 T. Cardiac (31)P MR spectra were acquired in vivo in healthy mice (n = 9) and in transverse aortic constricted (TAC) mice (n = 8) using respiratory-gated, cardiac-triggered 3D ISIS. Localization and potential signal contamination were assessed with (31)P MRS experiments in the anterior myocardial wall, liver, skeletal muscle and blood. For healthy hearts, results were validated against ex vivo biochemical assays. Effects of isoflurane anesthesia were assessed by measuring in vivo hemodynamics and blood gases. The myocardial energy status, assessed via the phosphocreatine (PCr) to adenosine 5'-triphosphate (ATP) ratio, was approximately 25% lower in TAC mice compared with controls (0.76 +/- 0.13 versus 1.00 +/- 0.15; P < 0.01). Localization with one-dimensional (1D) ISIS resulted in two-fold higher PCr/ATP ratios than measured with 3D ISIS, because of the high PCr levels of chest skeletal muscle that contaminate the 1D ISIS measurements. Ex vivo determinations of the myocardial PCr/ATP ratio (0.94 +/- 0.24; n = 8) confirmed the in vivo observations in control mice. Heart rate (497 +/- 76 beats/min), mean arterial pressure (90 +/- 3.3 mmHg) and blood oxygen saturation (96.2 +/- 0.6%) during the experimental conditions of in vivo (31)P MRS were within the normal physiological range. Our results show that respiratory-gated, cardiac-triggered 3D ISIS allows for non-invasive assessments of in vivo mouse myocardial energy homeostasis with (31)P MRS under physiological conditions. more...
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- 2015
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17. Administration of SGLT2 inhibitor empagliflozin against TNF-α induced endothelial dysfunction in human venous and arterial endothelial cells
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Uthman, L., primary, Homayr, A., additional, Hollmann, M.W., additional, Zuurbier, C.J., additional, Albrecht, M., additional, and Weber, N.C., additional
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- 2018
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18. Empagliflozin effects on ischemic contracture and I/R injury in isolated mouse hearts perfused with or without insulin
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Uthman, L., primary, Nederlof, R., additional, Eerbeek, O., additional, Baartscheer, A., additional, Buchholtz, N., additional, Coronel, R., additional, Hollmann, M.W., additional, Weber, N.C., additional, and Zuurbier, C.J., additional more...
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- 2018
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19. Empagliflozin partly restores impaired relaxation in human engineered heart tissue carrying a MYH7 mutation
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Wijnker, P.J.M., primary, Zuurbier, C.J., additional, and van der Velden, J., additional
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- 2018
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20. Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia/reperfusion of the intact heart
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Nederlof, R. (Rianne), Gürel-Gurevin, E. (Ebru), Eerbeek, O. (Otto), Xie, C. (Chaoqin), Deijs, G.S., Konkel, M. (Moritz), Hu, J. (Jun), Weber, N.C. (Nina), Schumacher, C. (Cees), Baartscheer, A. (Antonius), Mik, E.G. (Egbert), Hollmann, M.W. (Markus), Akar, F.G. (Fadi), Zuurbier, C.J. (Coert J.), Nederlof, R. (Rianne), Gürel-Gurevin, E. (Ebru), Eerbeek, O. (Otto), Xie, C. (Chaoqin), Deijs, G.S., Konkel, M. (Moritz), Hu, J. (Jun), Weber, N.C. (Nina), Schumacher, C. (Cees), Baartscheer, A. (Antonius), Mik, E.G. (Egbert), Hollmann, M.W. (Markus), Akar, F.G. (Fadi), and Zuurbier, C.J. (Coert J.) more...
- Abstract
Ischemia/reperfusion (I/R) of the heart becomes injurious when duration of the ischemic insult exceeds a certain threshold (approximately ≥20 min). Mitochondrial bound hexokinase II (mtHKII) protects against I/R injury, with the amount of mtHKII correlating with injury. Here, we examine whether mtHKII can induce the transition from non-injurious to injurious I/R, by detaching HKII from mitochondria during a non-injurious I/R interval. Additionally, we examine possible underlying mechanisms (increased reactive oxygen species (ROS), increased oxygen consumption (MVO2) and decreased cardiac energetics) associated with this transition. Langendorff perfused rat hearts were treated for 20 min with saline, TAT-only or 200 nM TAT-HKII, a peptide that translocates HKII from mitochondria. Then, hearts were exposed to non-injurious 15-min ischemia, followed by 30-min reperfusion. I/R injury was determined by necrosis (LDH release) and cardiac mechanical recovery. ROS were measured by DHE fluorescence. Changes in cardiac respiratory activity (cardiac MVO2 and efficiency and mitochondrial oxygen tension (mitoPO2) using protoporphyrin IX) and cardiac energetics (ATP, PCr, ∆GATP) were determined following peptide treatment. When exposed to 15-min ischemia, control hearts had no necrosis and 85% recovery of function. Conversely, TAT-HKII treatment resulted in significant LDH release and reduced cardiac recovery (25%), indicating injurious I/R. This was associated with increased ROS during ischemia and reperfusion. TAT-HKII treatment reduced MVO2 and improved energetics (increased PCr) before ischemia, without affecting MVO2/RPP ratio or mitoPO2. In conclusion, a reduction in mtHKII turns non-injurious I/R into injurious I/R. Loss of mtHKII was associated with increased ROS during ischemia and reperfusion, but not with increased MVO2 or decreased cardiac energetics before damage occurs. more...
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- 2016
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21. Effect of metformin pretreatment on myocardial injury during coronary artery bypass surgery in patients without diabetes (MetCAB): a double-blind, randomised controlled trial
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El Messaoudi, S., Nederlof, R., Zuurbier, C.J., Swieten, H.A. van, Pickkers, P., Noyez, L., Dieker, H.J., Coenen, M.J.H., Donders, A.R.T., Vos, A., Rongen, G.A.P.J.M., Riksen, N.P., El Messaoudi, S., Nederlof, R., Zuurbier, C.J., Swieten, H.A. van, Pickkers, P., Noyez, L., Dieker, H.J., Coenen, M.J.H., Donders, A.R.T., Vos, A., Rongen, G.A.P.J.M., and Riksen, N.P. more...
- Abstract
Contains fulltext : 155124.pdf (publisher's version ) (Closed access), BACKGROUND: During coronary artery bypass graft (CABG) surgery, ischaemia and reperfusion damage myocardial tissue, and increased postoperative plasma troponin concentration is associated with a worse outcome. We investigated whether metformin pretreatment limits cardiac injury, assessed by troponin concentrations, during CABG surgery in patients without diabetes. METHODS: We did a placebo-controlled, double-blind, single-centre study in an academic hospital in Nijmegen (Netherlands) in adult patients without diabetes undergoing an elective on-pump CABG procedure. We randomly assigned patients (1:1) in blocks of ten via a computer-generated randomisation sequence to either metformin hydrochloride (500 mg three times per day) or placebo (three times per day) for 3 days before surgery. The last dose was given roughly 3 h before surgery. Patients, investigators, trial staff, and the statistician were all masked to treatment allocation. The primary endpoint was the plasma concentration of high-sensitive troponin I at 6, 12, and 24 h postreperfusion after surgery, analysed in the per-protocol population with a mixed-model analysis using all these timepoints. Secondary endpoints included the occurrence of clinically relevant arrhythmias within 24 hours after reperfusion, the need for inotropic support, time to detubation, duration of stay in the intensive-care unit, and postoperative use of insulin. This study is registered with ClinicalTrials.gov, number NCT01438723. FINDINGS: Between Nov 8, 2011, and Nov 22, 2013, we randomly assigned 111 patients to treatment (57 to metformin and 54 to placebo). Five patients dropped out from the metformin group, and six from the placebo group. 52 patients in the metformin group and 48 patients in the placebo group were included in the per-protocol analysis. Geometric mean high-sensitivity troponin I increased from 0 mug/L to 3.67 mug/L (95% CI 3.06-4.41) with metformin and to 3.32 mug/L (2.75-4.01) with placebo at 6 h after reperfusio more...
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- 2015
22. Increased in vivo mitochondrial oxygenation with right ventricular failure induced by pulmonary arterial hypertension: Mitochondrial inhibition as driver of cardiac failure?
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Balestra, G. (Gianmarco), Mik, E.G. (Egbert), Eerbeek, O. (Otto), Specht, P. (Patricia), van der Laarse, W.J. (Willem J.), Zuurbier, C.J. (Coert J.), Balestra, G. (Gianmarco), Mik, E.G. (Egbert), Eerbeek, O. (Otto), Specht, P. (Patricia), van der Laarse, W.J. (Willem J.), and Zuurbier, C.J. (Coert J.) more...
- Abstract
Background: The leading cause of mortality due to pulmonary arterial hypertension (PAH) is failure of the cardiac right ventricle. It has long been hypothesized that during the development of chronic cardiac failure the heart becomes energy deprived, possibly due to shortage of oxygen at the level of cardiomyocyte mitochondria. However, direct evaluation of oxygen tension levels within the in vivo right ventricle during PAH is currently lacking. Here we directly evaluated this hypothesis by using a recently reported technique of oxygen-dependent quenching of delayed fluorescence of mitochondrial protoprophyrin IX, to determine the distribution of mitochondrial oxygen tension (mitoPO2) within the right ventricle (RV) subjected to progressive PAH.Methods: PAH was induced through a single injection of monocrotaline (MCT). Control (saline-injected), compensated RV hypertrophy (30 mg/kg MCT; MCT30), and RV failure (60 mg/kg MCT; MCT60) rats were compared 4 wk after treatment. The distribution of mitoPO2 within the RV was determined in mechanically-ventilated, anaesthetized animals, applying different inspired oxygen (FiO2) levels and two increment dosages of dobutamine.Results: MCT60 resulted in RV failure (increased mortality, weight loss, increased lung weight), MCT30 resulted in compensated RV hypertrophy. At 30% or 40% FiO2, necessary to obtain physiological arterial PO2 in the diseased animals, RV failure rats had significantly less mitochondria (15% of total mitochondria) in the 0-20 mmHg mitoPO2 range than hypertrophied RV rats (48%) or control rats (54%). Only when oxygen supply was reduced to 21% FiO2, resulting in low arterial PO2 for the MCT60 animals, or when oxygen demand increased with high dose dobutamine, the number of failing RV mitochondria with low oxygen became similar to control RV. In addition, metabolic enzyme analysis revealed similar mitochondrial mass, increa more...
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- 2015
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23. In vivo mouse myocardial P-31 MRS using three-dimensional image-selected in vivo spectroscopy (3D ISIS): technical considerations and biochemical validations
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Bakermans, A.J., Abdurrachim, D., van Nierop, B.J., Koeman, A., van der Kroon, I., Baartscheer, A, Schumacher, C.A., Strijkers, G.J., Houten, S.M., Zuurbier, C.J., Nicolay, K., Prompers, J.J., Bakermans, A.J., Abdurrachim, D., van Nierop, B.J., Koeman, A., van der Kroon, I., Baartscheer, A, Schumacher, C.A., Strijkers, G.J., Houten, S.M., Zuurbier, C.J., Nicolay, K., and Prompers, J.J. more...
- Published
- 2015
24. TAT-HKII Induced Reduction in Mitochondrial Bound Hexokinase II Increases Ischemia Reperfusion Injury by Increased Respiration and Increased Ros Levels
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Nederlof, R., primary, Gürel, E., additional, Xie, C., additional, Eerbeek, O., additional, Koeman, A., additional, Hollmann, M.W., additional, Southworth, R., additional, Akar, F.G., additional, Mik, E.G., additional, and Zuurbier, C.J., additional more...
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- 2014
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25. Deletion of the innate immune NLRP3 receptor abolishes cardiac ischemic preconditioning and is associated with decreased Il-6/STAT3 signaling
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Zuurbier, C.J., Jong, W.M., Eerbeek, O., Koeman, A., Pulskens, W.P.C., Butter, L.M., Leemans, J.C., Hollmann, M.W., Zuurbier, C.J., Jong, W.M., Eerbeek, O., Koeman, A., Pulskens, W.P.C., Butter, L.M., Leemans, J.C., and Hollmann, M.W. more...
- Abstract
Contains fulltext : 110810.pdf (publisher's version ) (Open Access), OBJECTIVE: Recent studies indicate that the innate immune system is not only triggered by exogenous pathogens and pollutants, but also by endogenous danger signals released during ischemia and necrosis. As triggers for the innate immune NLRP3 inflammasome protein complex appear to overlap with those for cardiac ischemia-reperfusion (I/R) and ischemic preconditioning (IPC), we explored the possibility that the NLRP3 inflammasome is involved in IPC and acute I/R injury of the heart. PRINCIPAL FINDINGS: Baseline cardiac performance and acute I/R injury were investigated in isolated, Langendorff-perfused hearts from wild-type (WT), ASC(-/-) and NLRP3(-/-) mice. Deletion of NLRP3 inflammasome components ASC(-/-) or NLRP3(-/-) did not affect baseline performance. The deletions exacerbated I/R-induced mechanical dysfunction, but were without effect on I/R-induced cell death. When subjected to IPC, WT and ASC(-/-) hearts were protected against I/R injury (improved function and less cell death). However, IPC did not protect NLRP3(-/-) hearts against I/R injury. NLRP3(-/-) hearts had significantly decreased cardiac IL-6 levels with a trend towards lower IL-1beta levels at end reperfusion, suggesting abrogation of IPC through diminished IL-6 and/or IL-1beta signaling. Subsequent experiments showed that neutralising IL-6 using an antibody against IL-6 abrogated IPC in WT hearts. However, inhibition of the IL-1r receptor with the IL-1 receptor inhibitor Anakinra (100 mg/L) did not abrogate IPC in WT hearts. Analysis of survival kinases after IPC demonstrated decreased STAT3 expression in NLRP3(-/-) hearts when compared to WT hearts. CONCLUSIONS: The data suggest that the innate immune NLRP3 protein, in an NLRP3-inflammasome-independent fashion, is an integral component of IPC in the isolated heart, possibly through an IL-6/STAT3 dependent mechanism. more...
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- 2012
26. Reduced hexokinase II impairs muscle function 2 weeks after ischemia-reperfusion through increased cell necrosis and fibrosis
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Smeele, K.M., Eerbeek, O., Schaart, G., Koeman, A., Bezemer, R., Nelson, J.K., Ince, C., Nederhof, R., Boek, M., Laakso, M., de Haan, A., Drost, M.R., Hollman, M.W., Zuurbier, C.J., Smeele, K.M., Eerbeek, O., Schaart, G., Koeman, A., Bezemer, R., Nelson, J.K., Ince, C., Nederhof, R., Boek, M., Laakso, M., de Haan, A., Drost, M.R., Hollman, M.W., and Zuurbier, C.J. more...
- Abstract
We previously demonstrated that hexokinase (HK) II plays a key role in the pathophysiology of ischemia-reperfusion (I/R) injury of the heart (Smeele et al. Circ Res 108: 1165-1169, 2011; Wu et al. Circ Res 108: 60-69, 2011). However, it is unknown whether HKII also plays a key role in I/R injury and healing thereafter in skeletal muscle, and if so, through which mechanisms. We used male wild-type (WT) and heterozygous HKII knockout mice (HKII more...
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- 2012
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27. Partial hexokinase II knockout results in acute ischemia-reperfusion damage in skeletal muscle of male, but not female, mice
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Smeele, K.M., Eerbeek, O., Koeman, A., Bezemer, R., Ince, C., Heikkinen, S., Laakso, M., de Haan, A., Schaart, G., Drost, M.R., Hollmann, M.W., Zuurbier, C.J., Smeele, K.M., Eerbeek, O., Koeman, A., Bezemer, R., Ince, C., Heikkinen, S., Laakso, M., de Haan, A., Schaart, G., Drost, M.R., Hollmann, M.W., and Zuurbier, C.J. more...
- Abstract
Cellular studies have demonstrated a protective role of mitochondrial hexokinase against oxidative insults. It is unknown whether HK protective effects translate to the in vivo condition. In the present study, we hypothesize that HK affects acute ischemia-reperfusion injury in skeletal muscle of the intact animal. Male and female heterozygote knockout HKII (HK more...
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- 2010
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28. In vivo mitochondrial oxygen tension measured by a delayed fluorescence lifetime technique
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Mik, E.G. (Egbert), Johannes, T. (Tanja), Zuurbier, C.J. (Coert Jozef), Heinen, A. (Andre), Houben-Weerts, J.H.P.M. (Judith), Balestra, G. (Gianmarco), Stap, J. (Jan), Beek, J.F. (Johan), Ince, C. (Can), Mik, E.G. (Egbert), Johannes, T. (Tanja), Zuurbier, C.J. (Coert Jozef), Heinen, A. (Andre), Houben-Weerts, J.H.P.M. (Judith), Balestra, G. (Gianmarco), Stap, J. (Jan), Beek, J.F. (Johan), and Ince, C. (Can) more...
- Abstract
Mitochondrial oxygen tension (mitoPO2) is a key parameter for cellular function, which is considered to be affected under various pathophysiological circumstances. Although many techniques for assessing in vivo oxygenation are available, no technique for measuring mitoPO2in vivo exists. Here we report in vivo measurement of mitoPO2and the recovery of mitoPO2histograms in rat liver by a novel optical technique under normal and pathological circumstances. The technique is based on oxygen-dependent quenching of the delayed fluorescence lifetime of protoporphyrin IX. Application of 5-aminolevulinic acid enhanced mitochondrial protoporphyrin IX levels and induced oxygen-dependent delayed fluorescence in various tissues, without affecting mitochondrial respiration. Using fluorescence microscopy, we demonstrate in isolated hepatocytes that the signal is of mitochondrial origin. The delayed fluorescence lifetime was calibrated in isolated hepatocytes and isolated perfused livers. Ultimately, the technique was applied to measure mitoPO2in rat liver in vivo. The results demonstrate mitoPO2values of ∼30-40 mmHg. mitoPO2was highly sensitive to small changes in inspired oxygen concentration around atmospheric oxygen level. Ischemia-reperfusion interventions showed altered mitoPO2distribution, which flattened overall compared to baseline conditions. The reported technology is scalable from microscopic to macroscopic applications, and its reliance on an endogenous compound greatly enhances its potential field of applications. more...
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- 2008
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29. Effects of in vivo like activation frequency on length dependent force generation of skeletal muscle fibre bundels
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Zuurbier, C.J., Lee de Groot, M.B.E., van der Laarse, W.J., Huijing, P.A.J.B.M., and Kinesiology
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- 1998
30. Postischemic Myocardial Metabolism
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Zuurbier, C.J., primary
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- 2003
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31. Eacpt-0032 - TAT-HKII Induced Reduction in Mitochondrial Bound Hexokinase II Increases Ischemia Reperfusion Injury by Increased Respiration and Increased Ros Levels
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Nederlof, R., Gürel, E., Xie, C., Eerbeek, O., Koeman, A., Hollmann, M.W., Southworth, R., Akar, F.G., Mik, E.G., and Zuurbier, C.J.
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- 2014
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32. Mitochondrial Response to Heart Rate Steps in Isolated Rabbit Heart Is Slowed After Myocardial Stunning
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Zuurbier, C.J., primary and van Beek, J.H.G.M., additional
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- 1997
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33. Mitochondrial Function is not Decreased in Stunned Papillary Muscle at 20°C
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Zuurbier, C.J., primary, Mast, F., additional, Elzinga, G., additional, and Van Beek, J.H.G.M., additional
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- 1997
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34. Mean sarcomere length-force relationship of rat muscle fibre bundles
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Zuurbier, C.J., primary, Heslinga, J.W., additional, Lee-de Groot, M.B.E., additional, and Van der Laarse, W.J., additional
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- 1995
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35. sInfluence of Muscle Shortening on the Geometry of Gastrocnemius Medialis Muscle of the Rat
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Zuurbier, C.J., primary and Huijing, P.A., additional
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- 1991
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36. Inhibition of the pentose phosphate pathway decreases ischemia–reperfusion-induced creatine kinase release in the heart
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Zuurbier, C.J., Eerbeek, O., Goedhart, P.T., Struys, E.A., Verhoeven, N.M., Jakobs, C., and Ince, C.
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METABOLISM , *ISCHEMIA , *NECROSIS , *REPERFUSION - Abstract
Objective: The oxidative pentose phosphate pathway (oxPPP) produces NADPH, which can be used to maintain glutathione in its reduced state (anti-oxidant; beneficial effects) or to produce radicals or nitric oxide (NO) through NADPH oxidase/NO synthase (detrimental effects). Changes in cytosolic redox status have been implicated in ischemic preconditioning (PC). This study investigates whether (1) PC affects mitochondrial redox state, (2) the oxPPP plays a protective or detrimental role in ischemia (I)–reperfusion (R) injury in the intact heart and (3) PPP is altered with PC. Methods: Isolated rat hearts were subjected to 40-min global I and 30-min R (CO, control). Ischemia was either preceded by three 5-min I/R periods (PC) and/or oxPPP inhibition by 6-aminonicotinamide (6AN) or NADPH oxidase/NO synthase inhibition by diphenyleneiodonium (DPI). NADH videofluorometry was used to determine mitochondrial redox state. PPP intermediates were determined in CO and PC hearts using tandem mass spectrometry. Results: PC reduced ischemic damage (creatine kinase, CK, release from 337±64 to 147±41 U/R/gdw) and contracture (from 59±5 to 31±3 mm Hg) and increased recovery of contractility (from 48±10% to 88±8%), as compared to CO. PC was without effect on NADH fluorometry. Inhibition of the oxPPP reduced injury (CK release: 91±24 U/R/gdw) to similar levels as PC, without improving contractility. Inhibition of NADPH oxidase/NO synthase mimicked the effects of oxPPP inhibition on injury (CK release: 140±22 U/R/gdw). Although levels of ribose-5P and (ribulose-5P+xylulose-5P) rose several fold during ischemia with minor changes in sedoheptulose-7P, demonstrating an active PPP in the heart, PC did not affect these levels. Conclusions: (1) PC can attenuate cardiac reperfusion injury without alterations in mitochondrial redox state; (2) inhibition of the oxPPP protects the heart against I/R-induced CK release; and (3) PC does not result in altered activity of the PPP. [Copyright &y& Elsevier] more...
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- 2004
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37. Functional heterogeneity of oxygen supply-consumption ratio in the heart.
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Zuurbier, C.J, van Iterson, M, and Ince, C
- Abstract
In this review, the regional heterogeneity of the oxygen supply-consumption ratio within the heart is discussed. This is an important functional parameter because it determines whether regions within the heart are normoxic or dysoxic. Although the heterogeneity of the supply side of oxygen has been primarily described by flow heterogeneity, the diffusional component of oxygen supply should not be ignored, especially at high resolution (tissue regions ≪ 1 g). Such oxygen diffusion does not seem to take place from arterioles or venules within the heart, but seems to occur between capillaries, in contrast to data recently obtained from other tissues. Oxygen diffusion may even become the primary determinant of oxygen supply during obstructed flow conditions. Studies aimed at modelling regional blood flow and oxygen consumption have demonstrated marked regional heterogeneity of oxygen consumption matched by flow heterogeneity. Direct, non-invasive indicators of the balance between oxygen supply and consumption include NADH videofluorimetry (mitochondrial energy state) and microvascular PO2 measurement by the Pd-porphyrin phosphorescence technique. These indicators have shown a relatively homogeneous distribution during physiological conditions supporting the notion of regional matching of oxygen supply with oxygen consumption. NADH videofluorimetry, however, has demonstrated large increases in functional heterogeneity of this ratio in compromised hearts (ischemia, hypoxia, hypertrophy and endotoxemia) with specific areas, referred to as microcirculatory weak units, predisposed to showing the first signs of dysoxia. It has been suggested that these weak units show the largest relative reduction in flow (independent of absolute flow levels) during compromising conditions, with dysoxia initially developing at the venous end of the capillary. [ABSTRACT FROM PUBLISHER] more...
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- 1999
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38. sInfluence of Muscle Shortening on the Geometry of Gastrocnemius Medialis Muscle of the Rat.
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Zuurbier, C.J. and Huijing, P.A.
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- 1991
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39. Heat production of the rat during the day as influenced by treadmill exercise.
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van Waversveld, J., Boekholt, H.A., Schreurs, V.V.A.M., Zuurbier, C.J., van Waversveld, J., Boekholt, H.A., Schreurs, V.V.A.M., and Zuurbier, C.J.
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- 1988
40. Heat production of the rat during the day as influenced by treadmill exercise
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Waversveld, J. van, primary, Boekholt, H.A., additional, Schreurs, V.V.A.M., additional, and Zuurbier, C.J., additional
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- 1988
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41. Therapy and mechanisms of cardiac ischemia-reperfusion injury
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Xiao, Yang, Hollmann, M.W., Preckel, B., Zuurbier, C.J., Hauck-Weber, N.C., Faculteit der Geneeskunde, Hollmann, Markus W., Preckel, Prof. dr., Benedikt, Zuurbier, Coert J., Hauck, Nina C., ACS - Microcirculation, Anesthesiology, and Graduate School more...
- Abstract
Acute myocardial infarction (AMI or heart attack), in which myocardial damage is primarily the result of ischemia-reperfusion (I/R) injury, remains the leading cause of morbidity and mortality worldwide. This thesis aims to explore therapeutic strategies for acute myocardial I/R injury and reveal the mechanisms underlying I/R injury. We first evaluated several promising cardioprotective compounds in an in vivo model employing clinically relevant anesthesia, showing that only nicotinamide riboside (NR; NAD precursor) reduced I/R injury in presence of clinic therapies. We then showed in the isolated heart that NR’s protection is through activation of glycolysis. Next, knowing that oxidative stress is a major initial triggers for I/R injury, a recently developed clinically-applicable antioxidant compound (KH176m) was examined and shown higher efficacy of cardioprotection than the classic antioxidant N-(2-mercaptopropionyl)-glycine. However, antioxidant protection was mostly shown for short, but not long, ischemia. Additionally, we examined the NOD-like receptors X1 (NLRX1), an anti-inflammatory mitochondrial innate immune receptor which was shown to protect against severe ischemia. By deep-diving into the mechanisms, NLRX1 was proven to be a novel constituent of the mitochondrial permeability transition pore (mPTP), regulate mitochondrial function, and indirectly contribute to cardioprotection by facilitating reperfusion injury salvage kinase (RISK) pathway activation. After 70 years of searching for the molecular identity of the mPTP, NLRX1 is a strong candidate to finally fill that knowledge gap. In conclusion, this thesis addresses several strategies for acute cardiac I/R injury and unravelling the underlying protecting mechanisms improves our understanding of the crucial pathological processes of I/R injury. more...
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- 2022
42. Direct cardiac and endothelial effects of sodium/glucose cotransporter 2 inhibitors and the role of the sodium/hydrogen exchanger 1
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Uthman, Laween, Hollmann, M.W., Preckel, B., Zuurbier, C.J., Hauck-Weber, N.C., Faculteit der Geneeskunde, Hollmann, Markus W., Preckel, Prof. dr. , Benedikt, Zuurbier, Coert J., Hauck, Nina C., ACS - Atherosclerosis & ischemic syndromes, ACS - Heart failure & arrhythmias, ACS - Diabetes & metabolism, Amsterdam Neuroscience - Neuroinfection & -inflammation, APH - Quality of Care, Anesthesiology, and Graduate School more...
- Abstract
Patients suffering from type 2 diabetes mellitus have at least twice as much chance to develop heart failure. A new class of anti-diabetic drug, named sodium/glucose cotransporter 2 inhibitors (SGLT2i’s), can reduce the risk of hospitalization for heart failure, an outcome that could not be attained by general cardiovascular risk factors reduction. This thesis provides insight that off-target and direct cardiac and endothelial actions of SGLT2i's may, at least partly, elicit the beneficial drug effects that could ultimately reduce the risk of heart failure. These mechanisms include changes in the cellular ion homeostasis, metabolism and inflammation and are to some extent modulated by the inhibition of the Na+/H+-exchanger. Our data show that SGLT2i's lower Na+/H+-exchanger activity and cytoplasmatic sodium levels in isolated cardiomyocytes and endothelial cells. In isolated hearts, SGLT2i empagliflozin caused 1) acute vasodilation in the healthy condition, 2) delayed the contracture onset during ischemia and 3) lowered lactate and increased α-ketoglutarate levels in the type 2 diabetic condition. Improved endothelial function, i.e. lower oxidative stress formation and increased nitric oxide bioavailability, during inflammation was observed with empagliflozin and dapagliflozin administration. Finally, this thesis shows that cytokine release during inflammation is dampened by canagliflozin through the reduction of hexokinase 2. In conclusion, SGLT2i’s provoke direct cardiac and endothelial effects that are to some extent modulated by inhibition of the Na+/H+-exchanger. more...
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- 2020
43. Inflammation and acute myocardial ischemia-reperfusion injury using a closed-chest mouse model
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Jong, W.M.C., Hollmann, M.W., de Winter, R.J., ten Cate, H., Zuurbier, C.J., and Faculteit der Geneeskunde
- Abstract
Acute myocardial ischemia- reperfusion (I/R) results in activation of the innate immune system. The immune reactions can be separately investigated by using mice deficient for a gene that codes for one of the immune components. However, the chest has to be opened to temporally occlude the left anterior descending artery. This intervention leads to the undesirable induction of the immune system, together with the I/R reactions. Therefore, we applied a closed-chest model with a preparative surgery one week before the actual I/R. We used the anesthetic mixture fentanyl- fluanisone- midazolam (FFM) during the preparative surgeries, because it resulted in stable mean arterial pressures and heart rates. Under FFM anesthesia, IL-6 deficient mice had smaller infarcts than wild type (WT) mice after 1h ischemia and 3 or 24h reperfusion. IL-1β and TNF-α levels peaked at 3h reperfusion, but showed no differences between the groups. Influx of neutrophils and activation of fibrin/ fibrinogen and tissue factor in the area at risk were also similar between the groups. Under pentobarbital anesthesia, Nlrp3 deficient and WT mice had similar infarct sizes after ½ and 1h ischemia and 3h reperfusion and after ischemic preconditioning (IPC). Myocardial NLRP3 expression was undetectable in the closed-chest model, whereas it was detectable in the open-chest model. In isolated Langendorff-perfused hearts, IPC resulted in protection of ASC deficient and WT but not of Nlrp3 deficient hearts. The Nlrp3 deficient hearts had significantly decreased IL-6 and STAT3 levels at end reperfusion, suggesting abrogation of IPC through diminished IL-6 signaling. more...
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- 2017
44. Mitochondrial hexokinase and ischemic sensitivity and metabolism of the heart
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Nederlof, Rianne, Hollmann, M.W., Preckel, B., Zuurbier, C.J., Hauck-Weber, N.C., Faculteit der Geneeskunde, Hollmann, Markus W., Preckel, Prof. dr., Benedikt, Zuurbier, Coert J., Hauck, Nina C., Graduate School, Amsterdam Neuroscience - Neuroinfection & -inflammation, and ACS - Heart failure & arrhythmias more...
- Abstract
The general aim of this thesis was to study the effects of hexokinase II (HKII) on cardiac ischemia/reperfusion (I/R) injury and metabolism. In cancer cells, increased binding of both HKI and HKII have been associated with the increased survival rate of these cells. In previous studies it has been observed that binding of HKII to the mitochondria (mtHKII) protects the heart and skeletal muscle against I/R injury. This thesis focused on elucidating the cellular mechanisms by which mtHKII protects the heart against I/R injury. We focused on the effect of a reduction in mtHKII on cardiac metabolism, oxygen consumption, reactive oxygen species and the correlation between HKII and cyclophilin D (CypD). In addition, this thesis studied whether cardioprotection by remote ischemic preconditioning (RIPC) and metformin treatment in cardiac surgical patients is associated with increased amounts of mtHKII. Taken together, this thesis shows that 1) low doses (200 nM) of the special peptide TAT-HKII can be used to study effects of mtHKII reduction in the heart, 2) a reduction in mtHKII turns non-injurious I/R into injurious I/R and is accompanied by increased reactive oxygen species (ROS) production at reperfusion, and increased energetics at baseline, 3) the cardioprotective effect of CypD deletion might, at least partly, be caused by increased mtHK activity, 4) an acute, but not chronic, decrease in mtHKII affects cardiac metabolism 5) glucose-only is insufficient substrate for the Langendorff perfused mouse heart, and 6) metformin treatment and RIPC in the absence of propofol are not cardioprotective in coronary artery bypass graft (CABG) surgery under the conditions used in this thesis. more...
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- 2017
45. Organ protection by the noble gas helium
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Smit, K.F., Preckel, B., Hollmann, M.W., Hauck-Weber, N.C., Zuurbier, C.J., and Faculteit der Geneeskunde
- Abstract
The aims of this thesis were to investigate whether helium induces preconditioning in humans, and to elucidate the mechanisms behind this possible protection. First, we collected data regarding organ protective effects of noble gases in general, and of helium in particular (chapters 1-3). In chapter 4 we demonstrated that helium inhalation in healthy volunteers had no negative side effects on the innate human immune system and the ability to respond to pathogens in vitro. After that, we showed that helium induces preconditioning in humans and protects against postischemic endothelial damage following forearm ischemia-reperfusion in healthy volunteers. (chapter 5). In chapter 6 we conducted a clinical trial, including 125 patients undergoing coronary artery bypass graft surgery, investigating whether helium affects signal transduction kinases (P38 mitogen-activated protein kinase, extracellular signal–regulated kinase-1/2, protein kinase C-ε or heat shock protein-27) or postoperative troponin release. The second aim of this thesis was to elucidate the mechanisms behind helium conditioning, which we investigated in cultured endothelial cells in vitro. In chapter 7 we demonstrate prolonged helium exposure (30 minutes) in endothelial cells surprisingly aggravated oxidative stress induced cell damage, increasing cell death. In chapter 9 we showed exposure to helium (20 minutes) increased cortical localization of F-actin fibers and decreases permeability via caveolin-1. Focusing on the possible effect of caveolin in the buoyant fraction (supernatant or plasma), we investigated whether plasma from healthy volunteers undergoing helium or ischemic conditioning protected endothelial cells against hypoxia in vitro (chapter 8 and 10). more...
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- 2017
46. Myocardial microcirculation and mitochondrial energetics in the isolated rat heart
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Ashruf, J.F., Ince, C., Zuurbier, C.J., Milstein, D.M.J., and Faculteit der Geneeskunde
- Abstract
Jesse Ashruf describes how the anatomy of the myocardial microcirculation determines the distribution pattern of oxygen to tissue and mitochondria, as evaluated with NADH- and Pd-porphyrin-videofluori-/phosphorimetry. In normal hearts this pattern reveals so-called weak microcirculatory units, originating at the capillary level, which are the first areas to become ischemic during episodes metabolic or circulatory stress. In hypertrophic Langendorff perfused hearts these weak areas are much larger indicating a disturbance at the arteriolar/arterial level. Cardiac work causes a decrease in mitochondrial NADH, in contrast to the view that increased mitochondrial respiration is driven by an increase in mitochondrial NADH. An explanation for the observation in some studies that increased work is associated with increased mitochondrial NADH is that increased work in the isolated perfused heart induces local ischemia, because the Langendorff perfused heart is borderline aerobic. NADH- and Pd-porphyrin-videofluori-/phosphorimetry can also be used to evaluate the mitochondrial redox state and microcirculatory oxygenation in vivo. Sepsis deteriorates myocardial mitochondrial oxidation, an effect that can be evaluated using NADH-videofluorimetry, making this a promising instrument to study the complex effect of sepsis on (micro-)circulation and mitochondrial function. Further advances in the understanding and treatment of shock must include a component on the (patho-)physiology of the microcirculation since in this functional anatomical compartment the most relevant mechanisms occur that cannot be understood by further advances in macrocirculatory knowledge. more...
- Published
- 2015
47. The role of mitochondrial hexokinase II in ischemia-reperfusion damage
- Author
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Smeele, K.M.A., Hollmann, M.W., Zuurbier, C.J., Eerbeek, O., and Faculteit der Geneeskunde
- Abstract
Bij een hartinfarct bepaalt de hoeveelheid onherstelbaar beschadigde hartcellen de prognose van de patiënt. Daarom is het noodzakelijk de schade te beperken. In kankercellen is bekend dat het eiwit hexokinase het afsterven van de cellen bemoeilijkt. Kirsten Smeele onderzocht of die beschermende werking bruikbaar kan zijn in het herstel na een hartinfarct. Het blijkt dat in hartspieren van muizen met minder hexokinase meer cellen doodgaan na zuurstoftekort; het eiwit blijkt cruciaal voor de levensvatbaarheid van hartcellen. Het ontrafelen van de onderliggende processen kan leiden tot nieuwe medicijnen die de schade na een hartinfarct door zuurstofgebrek beperken. more...
- Published
- 2012
48. Measuring microvascular and mitochondrial oxygen tension: novel techniques for studying tissue oxygenation
- Author
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Mik, E.G., Ince, C., Zuurbier, C.J., and Faculteit der Geneeskunde
- Abstract
This thesis describes the implementation of novel approaches for measuring tissue oxygenation based on oxygen-dependent quenching of the triplet-state lifetime of porphyrins. Ultimately we created a tool for assessment of mitochondrial oxygen tension in vivo. The first measurements indicate much higher mitoPO2 values than generally expected. These findings come in an era of new insights in cellular oxygen sensing and oxygen-dependence of gene expression and metabolism. The described methods are expected to be a valuable addition to the arsenal of tools available to scientist for unraveling the mechanisms of oxygen delivery and consumption under various pathophysiological circumstances. Oxygen is again important, as it has always been more...
- Published
- 2011
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