title: Proteomic insights into chronic anthracycline cardiotoxicity.
abstract: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. sterbam@lfhk.cuni.cz
authors.forename: Martin
authors.initials: M
authors.lastname: Stěrba
authors.forename: Olga
authors.initials: O
authors.lastname: Popelová
authors.forename: Juraj
authors.initials: J
authors.lastname: Lenčo
authors.forename: Alena
authors.initials: A
authors.lastname: Fučíková
authors.forename: Eva
authors.initials: E
authors.lastname: Brčáková
authors.forename: Yvona
authors.initials: Y
authors.lastname: Mazurová
authors.forename: Eduard
authors.initials: E
authors.lastname: Jirkovský
authors.forename: Tomáš
authors.initials: T
authors.lastname: Simůnek
authors.forename: Michaela
authors.initials: M
authors.lastname: Adamcová
authors.forename: Stanislav
authors.initials: S
authors.lastname: Mičuda
authors.forename: Jiří
authors.initials: J
authors.lastname: Stulík
authors.forename: Vladimír
authors.initials: V
authors.lastname: Geršl
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000633:toxicity*; D015153:Blotting, Western; D003630:Daunorubicin / Q000633:toxicity; D004452:Echocardiography; D015180:Electrophoresis, Gel, Two-Dimensional; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced* / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D008315:Malondialdehyde / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D040901:Proteomics; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019210:Troponin I / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D024101:Mitochondrial Proteins; D019210:Troponin I; D014746:Vimentin; D008315:Malondialdehyde; D003630:Daunorubicin