Study summary · research use only
AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study in rats examined whether AICAR (5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside), an AMPK activator, could prevent cardiac decline in a chronic intravenous rat model of doxorubicin (DOX)-induced heart failure (DOX-HF). The abstract reports AICAR was associated with improved cardiac systolic function and improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number and without observable AMPK activation. AICAR was also associated with prevention of myocardial mass loss, which RNAseq analysis suggested may relate to normalization of ribosome-function and protein-synthesis pathways impaired in DOX-treated rat hearts, as well as prevention of dyslipidemia and excessive body-weight loss in DOX-treated rats. The authors state it remains unclear whether AICAR's cardioprotective effect occurred through cardiac or extra-cardiac AMPK activation or an AMPK-independent pathway.
Abstract
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.
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