Narrow time window of metabolic changes associated with transition to overt heart failure in Tgaq*44 mice
| Autor: | Elżbieta Czarnowska, Ryszard T. Smolenski, Dorota Domal-Kwiatkowska, Urszula Tyrankiewicz, Beata Pająk, Marta Toczek, Anna Ratajska, Joanna Bierła, Ulrike Mende, Stefan Chlopicki |
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| Rok vydání: | 2016 |
| Předmět: |
CD36 Antigens
0301 basic medicine Genetically modified mouse medicine.medical_specialty CD36 heart failure structural remodeling Mice Transgenic 030204 cardiovascular system & hematology PPARα Muscle hypertrophy Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine metabolic remodeling Internal medicine Lipid droplet medicine Animals Myocytes Cardiac PPAR alpha Glycolysis Heart Failure Pharmacology Glucose Transporter Type 4 Carnitine O-Palmitoyltransferase Cell Death biology Glycogen Myocardium Fatty Acids Age Factors Hypertrophy General Medicine medicine.disease 030104 developmental biology Endocrinology chemistry Heart failure biology.protein GTP-Binding Protein alpha Subunits Gq-G11 hypertrophy Flux (metabolism) |
| Zdroj: | Pharmacological Reports. 68:707-714 |
| ISSN: | 1734-1140 |
| DOI: | 10.1016/j.pharep.2016.03.013 |
| Popis: | Background The timing and consequences of alternations in substrate utilization in heart failure (HF) and their relationship with structural changes remain unclear. This study aimed to analyze metabolic changes associated with transition to overt heart failure in transgenic mouse model of HF resulting from cardiac-specific overexpression of constitutively active Gα q *. Methods Structural changes quantified by morphometry, relative cardiac mRNA and protein expression of PPARα, FAT/CD36, CPT-1, GLUT-4 and glycolytic efficiency following administration of 1- 13 C glucose were investigated in 4–14-month-old Tgα q *44 mice (TG), compared with age-matched FVB wild type mice (WT). Results Initial hypertrophy in TG (4–10-month of age) was featured by an accelerated glycolytic pathway that was not accompanied by structural changes in cardiomyocytes. In 10-month-old TG, cardiomyocyte elongation and hypertrophic remodeling and increased glycolytic flux was accompanied by relatively low expression of FAT/CD36, CPT-1 and PPARα. During the transition phase (12-month-old TG), a pronounced increase in PPARα with an increase in relative fatty acid (FA) flux was associated with anomalies of cardiomyocytes with accumulation of lipid droplets and glycogen as well as cell death. At the stage of overt heart failure (14-month-old TG), an accelerated glycolytic pathway with a decline in FA oxidation was accompanied by further structural changes. Conclusion Tgα q *44 mice display three distinct phases of metabolic/structural changes during hypertrophy and progression to HF, with relatively short period of increase in FA metabolism, highlighting a narrow metabolic changes associated with transition to overt heart failure in Tgaq*44 mice that have therapeutic significance. |
| Databáze: | OpenAIRE |
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