AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats.

Autor: Choksey A; Department of Physiology Anatomy and Genetics, University of Oxford, UK., Carter RD; Department of Physiology Anatomy and Genetics, University of Oxford, UK; Doctoral Training Centre, University of Oxford, Keble Road, Oxford, OX1 3NP, UK., Thackray BD; Department of Physiology Anatomy and Genetics, University of Oxford, UK., Ball V; Department of Physiology Anatomy and Genetics, University of Oxford, UK., Kennedy BWC; Department of Physiology Anatomy and Genetics, University of Oxford, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK., Ha LHT; Department of Pharmacology, University of Oxford, UK., Sharma E; Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Dr, Headington, Oxford OX3 7BN, UK., Broxholme J; Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Dr, Headington, Oxford OX3 7BN, UK., Castro-Guarda M; Department of Physiology Anatomy and Genetics, University of Oxford, UK., Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, UK., Heather LC; Department of Physiology Anatomy and Genetics, University of Oxford, UK., Tyler DJ; Department of Physiology Anatomy and Genetics, University of Oxford, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK., Timm KN; Department of Physiology Anatomy and Genetics, University of Oxford, UK; Department of Pharmacology, University of Oxford, UK. Electronic address: kerstin.timm@pharm.ox.ac.uk.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2024 Jun; Vol. 191, pp. 12-22. Date of Electronic Publication: 2024 Apr 21.
DOI: 10.1016/j.yjmcc.2024.04.011
Abstrakt: Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to heart failure (HF). Impaired mitochondrial function is thought to be key factor driving progression into HF. We have previously shown in a rat model of DOX-HF that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and energy metabolism, including fatty acid oxidation. We hypothesised that AMPK activation could restore mitochondrial function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this chronic intravenous rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number, and in the absence of observable AMPK-activation. In addition, we found that AICAR prevented loss of myocardial mass. RNAseq analysis showed that this may be driven by normalisation of pathways associated with ribosome function and protein synthesis, which are impaired in DOX-treated rat hearts. AICAR furthermore prevented dyslipidemia and excessive body-weight loss in DOX-treated rats, which may contribute to preservation of myocardial mass. Though it is unclear whether AICAR exerted its cardioprotective effect through cardiac or extra-cardiac AMPK-activation or via an AMPK-independent effect, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.
Competing Interests: Declaration of competing interest Conflict of Interest: none declared.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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