AICAR-cardioprotection in doxorubicin-induced heart failure in rats

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to functional cardiac decline and ultimately, congestive heart failure (HF). Impaired mitochondrial function and energetics are thought to be key factors driving progression into HF. We have previously shown in a rat model of chronic intravenous DOX-administration 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 oxidative metabolism, including fatty acid oxidation. We hypothesized that AMPK activation could restore mitochondrial number and 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-ß-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this clinically relevant rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. This was associated with normalisation of substrate supply to the heart, as AICAR prevented DOX-induced dyslipidaemia. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number. In addition, we found that AICAR reduced the degree of myocardial atrophy, and RNAseq analysis showed that this was driven by normalisation of protein synthesis pathways, which are impaired in DOX-treated rat hearts. Taken together, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass. Overall design: We conducted RNASeq using mRNA extracted from rat hearts to elucidate the effect of doxorubicin on the heart and the cardioprotective effect of AICAR in this setting. Rats were 250g at the start of the treatment protocol. Tissues were collected post five weekly intavenous injections of either sterile saline (n=6) or 3mg/kg/week doxorubicin and subcutanous saline (n=6) or subcutaneous 0.5g/kg AICAR (n=6). Hearts were excised under deep isoflurane anaesthesia and rapidly frozen with liquid-nitrogen cooled Wollenberger tongs. Total mRNA was extracted with a Qiagen RNeasy fibrous tissue mini kit.