Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion
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| Titel: | Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion |
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| Autoren: | Yong Seon Choi, Ana Barbosa Marcondes de Mattos, Dan Shao, Tao Li, Miranda Nabben, Maengjo Kim, Wang Wang, Rong Tian, Stephen C. Kolwicz |
| Weitere Verfasser: | College of Medicine, Dept. of Anesthesiology and Pain Medicine, Yong Seon Choi, Ana Barbosa Marcondes de Mattos, Dan Shao, Tao Li, Miranda Nabben, Maengjo Kim, WangWang, Rong Tian, Stephen C. Kolwicz, Choi, Yong Seon |
| Quelle: | Journal of Molecular and Cellular Cardiology. 100:64-71 |
| Verlagsinformationen: | Elsevier BV, 2016. |
| Publikationsjahr: | 2016 |
| Schlagwörter: | Myocardium/pathology, Male, 0301 basic medicine, Oxidative Stress/genetics, Mice, 0302 clinical medicine, Diastole, [90] Lipid and lipoprotein metabolism, Ventricular Dysfunction, Mice, Knockout, Organelle Biogenesis, Angiotensin II, Fatty Acids, Cardiomegaly/genetics, Lipids, Magnetic Resonance Imaging, 3. Good health, Echocardiography, Myocardium/metabolism, Cardiomegaly/metabolism, Cardiomegaly/physiopathology, [145] genetically altered mice, [105] Contractile function, Ventricular Dysfunction/genetics, Oxidation-Reduction, Acetyl-CoA Carboxylase/deficiency, Knockout, Myocardium/ultrastructure, Cardiomegaly, ACC2, Angiotensin II/administration & dosage, Oxidation-Reduction/drug effects, 03 medical and health sciences, Cardiomegaly/diagnosis, Animals, Diastole/drug effects, Energy Metabolism/genetics, Animal, [107] Biochemistry and metabolism, Myocardium, [140] energy metabolism, Hypertrophy, Fibrosis, Fatty Acids/metabolism, Disease Models, Animal, Oxidative Stress, Disease Models, Ventricular Dysfunction/drug therapy, Ventricular Dysfunction/metabolism, Energy Metabolism, Cardiac metabolism, Gene Deletion, Acetyl-CoA Carboxylase |
| Beschreibung: | Diastolic dysfunction is a common feature in many heart failure patients with preserved ejection fraction and has been associated with altered myocardial metabolism in hypertensive and diabetic patients. Therefore, metabolic interventions to improve diastolic function are warranted. In mice with a germline cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2), systolic dysfunction induced by pressure-overload was prevented by maintaining cardiac fatty acid oxidation (FAO). However, it has not been evaluated whether this strategy would prevent the development of diastolic dysfunction in the adult heart.To test the hypothesis that augmenting cardiac FAO is protective against angiotensin II (AngII)-induced diastolic dysfunction in an adult mouse heart.We generated a mouse model to induce cardiac-specific deletion of ACC2 in adult mice. Tamoxifen treatment (20mg/kg/day for 5days) was sufficient to delete ACC2 protein and increase cardiac FAO by 50% in ACC2 flox/flox-MerCreMer+ mice (iKO). After 4weeks of AngII (1.1mg/kg/day), delivered by osmotic mini-pumps, iKO mice showed normalized E/E' and E'/A' ratios compared to AngII treated controls (CON). The prevention of diastolic dysfunction in iKO-AngII was accompanied by maintained FAO and reduced glycolysis and anaplerosis. Furthermore, iKO-AngII hearts had a~50% attenuation of cardiac hypertrophy and fibrosis compared to CON. In addition, maintenance of FAO in iKO hearts suppressed AngII-associated increases in oxidative stress and sustained mitochondrial respiratory complex activities.These data demonstrate that impaired FAO is a contributor to the development of diastolic dysfunction induced by AngII. Maintenance of FAO in this model leads to an attenuation of hypertrophy, reduces fibrosis, suppresses increases in oxidative stress, and maintains mitochondrial function. Therefore, targeting mitochondrial FAO is a promising therapeutic strategy for the treatment of diastolic dysfunction. |
| Publikationsart: | Article |
| Sprache: | English |
| ISSN: | 0022-2828 |
| DOI: | 10.1016/j.yjmcc.2016.09.001 |
| Zugangs-URL: | https://europepmc.org/articles/pmc5154855?pdf=render https://pubmed.ncbi.nlm.nih.gov/27693463 https://cris.maastrichtuniversity.nl/en/publications/8c507c04-a284-404e-a551-98b88604aefd https://doi.org/10.1016/j.yjmcc.2016.09.001 https://www.sciencedirect.com/science/article/abs/pii/S0022282816303455 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154855 https://core.ac.uk/display/91194508 http://www.ncbi.nlm.nih.gov/pubmed/27693463 https://www.narcis.nl/publication/RecordID/oai%3Acris.maastrichtuniversity.nl%3Apublications%2F8c507c04-a284-404e-a551-98b88604aefd https://www.jmmc-online.com/article/S0022-2828(16)30345-5/fulltext |
| Rights: | Elsevier TDM CC BY NC ND |
| Dokumentencode: | edsair.doi.dedup.....c69ddea2d345bd5e1951264ad0c709b5 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Diastolic dysfunction is a common feature in many heart failure patients with preserved ejection fraction and has been associated with altered myocardial metabolism in hypertensive and diabetic patients. Therefore, metabolic interventions to improve diastolic function are warranted. In mice with a germline cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2), systolic dysfunction induced by pressure-overload was prevented by maintaining cardiac fatty acid oxidation (FAO). However, it has not been evaluated whether this strategy would prevent the development of diastolic dysfunction in the adult heart.To test the hypothesis that augmenting cardiac FAO is protective against angiotensin II (AngII)-induced diastolic dysfunction in an adult mouse heart.We generated a mouse model to induce cardiac-specific deletion of ACC2 in adult mice. Tamoxifen treatment (20mg/kg/day for 5days) was sufficient to delete ACC2 protein and increase cardiac FAO by 50% in ACC2 flox/flox-MerCreMer+ mice (iKO). After 4weeks of AngII (1.1mg/kg/day), delivered by osmotic mini-pumps, iKO mice showed normalized E/E' and E'/A' ratios compared to AngII treated controls (CON). The prevention of diastolic dysfunction in iKO-AngII was accompanied by maintained FAO and reduced glycolysis and anaplerosis. Furthermore, iKO-AngII hearts had a~50% attenuation of cardiac hypertrophy and fibrosis compared to CON. In addition, maintenance of FAO in iKO hearts suppressed AngII-associated increases in oxidative stress and sustained mitochondrial respiratory complex activities.These data demonstrate that impaired FAO is a contributor to the development of diastolic dysfunction induced by AngII. Maintenance of FAO in this model leads to an attenuation of hypertrophy, reduces fibrosis, suppresses increases in oxidative stress, and maintains mitochondrial function. Therefore, targeting mitochondrial FAO is a promising therapeutic strategy for the treatment of diastolic dysfunction. |
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| ISSN: | 00222828 |
| DOI: | 10.1016/j.yjmcc.2016.09.001 |