Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
J Mol Cell Cardiol. 2011 May;50(5):849-62. doi: 10.1016/j.yjmcc.2011.01.018. Epub 2011 Jan 31.
Chronic anthracycline cardiotoxicity is a feared complication of cancer chemotherapy. However, despite several decades of primarily hypothesis-driven research, the molecular basis of this phenomenon remains poorly understood. The aim of this study was to obtain integrative molecular insights into chronic anthracycline cardiotoxicity and the resulting heart failure. Cardiotoxicity was induced in rabbits (daunorubicin 3mg/kg, weekly, 10weeks) and changes in the left ventricular proteome were analyzed by 2D-DIGE. The protein spots with significant changes (p<0.01, >1.5-fold) were identified using MALDI-TOF/TOF. Key data were corroborated by immunohistochemistry, qRT-PCR and enzyme activity determination and compared with functional, morphological and biochemical data. The most important alterations were found in mitochondria - especially in proteins crucial for oxidative phosphorylation, energy channeling, antioxidant defense and mitochondrial stress. Furthermore, the intermediate filament desmin, which interacts with mitochondria, was determined to be distinctly up-regulated and disorganized in its expression pattern. Interestingly, the latter changes reflected the intensity of toxic damage in whole hearts as well as in individual cells. In addition, a marked drop in myosin light chain isoforms, activation of proteolytic machinery (including the proteasome system), increased abundance of chaperones and proteins involved in chaperone-mediated autophagy, membrane repair as well as apoptosis were found. In addition, dramatic changes in proteins of basement membrane and extracellular matrix were documented. In conclusion, for the first time, the complex proteomic signature of chronic anthracycline cardiotoxicity was revealed which enhances our understanding of the basis for this phenomenon and it may enhance efforts in targeting its reduction.
慢性蒽环类药物心脏毒性是癌症化疗的一种可怕并发症。然而，尽管几十年来主要是基于假说的研究，但这种现象的分子基础仍知之甚少。本研究旨在获得对慢性蒽环类药物心脏毒性和由此导致的心力衰竭的综合分子见解。通过 2D-DIGE 分析兔的心脏毒性（柔红霉素 3mg/kg，每周一次，共 10 周）和左心室蛋白质组的变化。使用 MALDI-TOF/TOF 鉴定具有显著变化的蛋白质斑点（p<0.01，>1.5 倍）。通过免疫组织化学、qRT-PCR 和酶活性测定对关键数据进行了验证，并与功能、形态和生化数据进行了比较。最重要的变化发生在线粒体中-特别是在对氧化磷酸化、能量通道、抗氧化防御和线粒体应激至关重要的蛋白质中。此外，与线粒体相互作用的中间丝蛋白 desmin 被确定为明显上调且表达模式紊乱。有趣的是，后一种变化反映了整个心脏以及单个细胞中毒性损伤的强度。此外，肌球蛋白轻链同工型明显减少，蛋白酶体系统（包括蛋白酶体系统）被激活，伴侣蛋白和伴侣介导的自噬、膜修复以及细胞凋亡相关蛋白的丰度增加。此外，还记录了基底膜和细胞外基质蛋白质的剧烈变化。总之，首次揭示了慢性蒽环类药物心脏毒性的复杂蛋白质组学特征，这增强了我们对这种现象基础的理解，并可能增强减少其毒性的努力。
