文章：

蒽环类药物心脏毒性的初始阶段涉及心脏成纤维细胞活化与代谢转换

Initial Phase of Anthracycline Cardiotoxicity Involves Cardiac Fibroblasts Activation and Metabolic Switch

原文发布日期：21 December 2023

DOI: 10.3390/cancers16010053

类型: Article

开放获取: 是

英文摘要：

The application of doxorubicin (DOX) is hampered by cardiotoxicity, with diastolic dysfunction as the earliest manifestation. Fibrosis leads to impaired relaxation, but the mechanisms that operate shortly after DOX exposure are not clear. We asked whether the activation of cardiac fibroblasts (CFs) anticipates myocardial dysfunction and evaluated the effects of DOX on CF metabolism. CFs were isolated from the hearts of rats after the first injection of DOX. In another experiment, CFs were exposed to DOX in vitro. Cell phenotype and metabolism were determined. Early effects of DOX consisted of diastolic dysfunction and unchanged ejection fraction. Markers of pro-fibrotic remodeling and evidence of CF transformation were present immediately after treatment completion. Oxygen consumption rate and extracellular acidification revealed an increased metabolic activity of CFs and a switch to glycolytic energy production. These effects were consistent in CFs isolated from the hearts of DOX-treated animals and in naïve CFs exposed to DOX in vitro. The metabolic switch was paralleled with the phenotype change of CFs that upregulated markers of myofibroblast differentiation and the activation of pro-fibrotic signaling. In conclusion, the metabolic switch and activation of CFs anticipate DOX-induced damage and represent a novel target in the early phase of anthracycline cardiomyopathy.

摘要翻译： 

阿霉素（DOX）的应用受限于其心脏毒性，其中舒张功能障碍是最早出现的表现。纤维化导致心肌松弛能力受损，但阿霉素暴露后短期内起作用的机制尚不明确。本研究旨在探讨心脏成纤维细胞（CFs）的激活是否早于心肌功能障碍的发生，并评估阿霉素对CF代谢的影响。实验首次注射阿霉素后从大鼠心脏分离CFs；另设体外实验使CFs直接暴露于阿霉素。通过检测细胞表型与代谢状态发现：阿霉素早期效应表现为舒张功能障碍而射血分数不变；治疗结束后立即出现促纤维化重塑标志物及CF转化证据；耗氧率与细胞外酸化率显示CFs代谢活性增强并转向糖酵解供能模式。这些效应在阿霉素治疗动物心脏分离的CFs与体外阿霉素暴露的初始CFs中表现一致。代谢转换伴随CFs表型变化，表现为肌成纤维细胞分化标志物上调及促纤维化信号通路激活。结论表明，CFs的代谢转换与激活先于阿霉素诱导的心肌损伤，可作为蒽环类药物心肌病早期干预的新靶点。

原文链接：

Initial Phase of Anthracycline Cardiotoxicity Involves Cardiac Fibroblasts Activation and Metabolic Switch