Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/19848
Título
Anthracycline Cardiotoxicity Induces Progressive Changes in Myocardial Metabolism and Mitochondrial Quality Control: Novel Therapeutic Target.
Autor(es)
Díaz-Guerra, Anabel | Villena-Gutierrez, Rocio CNIC | Clemente-Moragón, Agustín | Gomez, Monica CNIC | Oliver, Eduardo CNIC | Fernández-Tocino, Miguel | Galan-Arriola, Carlos CNIC | Cádiz, Laura | Ibáñez, Borja CNIC
Fecha de publicación
2024-04
Cita
JACC CardioOncol. 2024 Apr 16;6(2):217-232.
Idioma
Inglés
Tipo de documento
journal article
Resumen
BACKGROUND
Anthracycline-induced cardiotoxicity (AIC) debilitates quality of life in cancer survivors. Serial characterizations are lacking of the molecular processes occurring with AIC.
OBJECTIVES
The aim of this study was to characterize AIC progression in a mouse model from early (subclinical) to advanced heart failure stages, with an emphasis on cardiac metabolism and mitochondrial structure and function.
METHODS
CD1 mice received 5 weekly intraperitoneal doxorubicin injections (5 mg/kg) and were followed by serial echocardiography for 15 weeks. At 1, 9, and 15 weeks after the doxorubicin injections, mice underwent fluorodeoxyglucose positron emission tomography, and hearts were extracted for microscopy and molecular analysis.
RESULTS
Cardiac atrophy was evident at 1 week post-doxorubicin (left ventricular [LV] mass 117 ± 26 mg vs 97 ± 25 mg at baseline and 1 week, respectively; P < 0.001). Cardiac mass nadir was observed at week 3 post-doxorubicin (79 ± 16 mg; P = 0.002 vs baseline), remaining unchanged thereafter. Histology confirmed significantly reduced cardiomyocyte area (167 ± 19 μm2 in doxorubicin-treated mice vs 211 ± 26 μm2 in controls; P = 0.004). LV ejection fraction declined from week 6 post-doxorubicin (49% ± 9% vs 61% ± 9% at baseline; P < 0.001) until the end of follow-up at 15 weeks (43% ± 8%; P < 0.001 vs baseline). At 1 week post-doxorubicin, when LV ejection fraction remained normal, reduced cardiac metabolism was evident from down-regulated markers of fatty acid oxidation and glycolysis. Metabolic impairment continued to the end of follow-up in parallel with reduced mitochondrial adenosine triphosphate production. A transient early up-regulation of nutrient-sensing and mitophagy markers were observed, which was associated with mitochondrial enlargement. Later stages, when mitophagy was exhausted, were characterized by overt mitochondrial fragmentation.
CONCLUSIONS
Cardiac atrophy, global hypometabolism, early transient-enhanced mitophagy, biogenesis, and nutrient sensing constitute candidate targets for AIC prevention.
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