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Cellular, mitochond...
Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement
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- Heinonen, Ilkka, 1982- (author)
- Högskolan i Halmstad,Rydberglaboratoriet för tillämpad naturvetenskap (RLAS),Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands, Turku PET Centre, University of Turku, Turku, Finland, Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland
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- Sorop, Oana (author)
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands
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- van Dalen, Bas M. (author)
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands
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- Wüst, Rob C. I. (author)
- Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Amsterdam Movement Sciences, VU University, Amsterdam, The Netherlands
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- van de Wouw, Jens (author)
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands
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- de Beer, Vincent J. (author)
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands
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- Octavia, Yanti (author)
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands
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- van Duin, Richard W. B. (author)
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands
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- Hoogstrate, Youri (author)
- Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands
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- Blonden, Lau (author)
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands
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- Alkio, Milla (author)
- Department of Biology, University of Turku and Turku University Hospital, Turku, Finland
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- Anttila, Katja (author)
- Department of Biology, University of Turku and Turku University Hospital, Turku, Finland
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- Stubbs, Andrew (author)
- 2 Clinical Bioinformatics Unit, Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
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- van der Velden, Jolanda (author)
- Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands, Netherlands Heart Institute, Utrecht, The Netherlands
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- Merkus, Daphne (author)
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands, Walter Brendel Center of Experimental Medicine (WBex), LMU Munich, Munich, Germany, German Center for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance (MHA), Munich, Germany
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- Duncker, Dirk J. (author)
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands
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(creator_code:org_t)
- 2020-08-06
- 2020
- English.
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In: Scientific Reports. - London : Nature Publishing Group. - 2045-2322. ; 10:1
- Related links:
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https://doi.org/10.1...
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Abstract
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- The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Göttingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitrosoredox balance, increased superoxide production—principally due to endothelial nitric oxide synthase (eNOS) uncoupling—reduced nitric oxide (NO) production, alterations in myocardial gene-expression— particularly genes related to glucose and fatty acid metabolism—and mitochondrial dysfunction. These abnormalities were accompanied by increased passive force of isolated cardiomyocytes, and impaired LV diastolic function, evidenced by reduced LV peak untwist velocity and increased E/e′. However, LV weight, volume, collagen content, and cardiomyocyte cross-sectional area were unchanged at this stage of DMetD. In conclusion, DMetD, in a clinically relevant large-animal model results in myocardial oxidative stress, eNOS uncoupling and reduced NO production, together with an altered metabolic gene expression profle and mitochondrial dysfunction. These molecular alterations are associated with stifening of the cardiomyocytes and early diastolic dysfunction before any structural cardiac remodeling occurs. Therapies should be directed to ameliorate these early DMetDinduced myocardial changes to prevent the development of overt cardiac failure. © 2020, The Author(s).
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- Preserved Ejection Fraction
- Heart-Failure
- Myocardial Stiffness
- Signaling Pathway
- Mechanisms
- Contributes
- Inhibition
- Oxidation
- Health
- Mice
Publication and Content Type
- ref (subject category)
- art (subject category)
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Heinonen, Ilkka, ...
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Sorop, Oana
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van Dalen, Bas M ...
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Wüst, Rob C. I.
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van de Wouw, Jen ...
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de Beer, Vincent ...
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Octavia, Yanti
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van Duin, Richar ...
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Hoogstrate, Your ...
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Blonden, Lau
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Alkio, Milla
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Anttila, Katja
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Stubbs, Andrew
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van der Velden, ...
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Merkus, Daphne
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Duncker, Dirk J.
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Halmstad University