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.
摘要：
多柔比星（DOX）是一种广泛使用的化学治疗剂，可引起严重的心脏毒性副作用，导致心力衰竭（HF）。线粒体功能受损被认为是驱动进展为HF的关键因素。我们先前已经在DOX-HF的大鼠模型中表明，射血分数降低的心力衰竭与线粒体丢失和功能障碍相关。腺苷一磷酸依赖性激酶（AMPK）是一种细胞能量传感器，调节线粒体生物发生和能量代谢，包括脂肪酸氧化。我们假设AMPK激活可以恢复线粒体功能，因此是预防DOX-HF的新型心脏保护策略。因此,我们着手评估5-氨基咪唑-4-甲酰胺1-β-D-呋喃核糖苷(AICAR)AMPK的激活剂,可以预防这种慢性静脉内DOX-HF大鼠模型的心功能下降。根据我们的假设,AICAR改善心脏收缩功能。AICAR进一步改善心脏线粒体脂肪酸氧化，与线粒体数量无关，并且在没有可观察到的AMPK激活的情况下。此外,我们发现AICAR可以预防心肌质量的损失。RNAseq分析显示，这可能是由与核糖体功能和蛋白质合成相关的通路正常化驱动的。在DOX处理的大鼠心脏中受损。AICAR还预防了DOX治疗大鼠的血脂异常和体重过度下降，这可能有助于保持心肌质量。虽然尚不清楚AICAR是否通过心脏或心脏外AMPK激活或通过AMPK非依赖性作用发挥其心脏保护作用，这些结果表明,AICAR有望在DOX-HF中用作心脏保护剂,以保护心脏功能和质量.
