Abstract
Chronic anthracycline cardiotoxicity is a serious clinical issue with well characterized functional and histopathological hallmarks. However, molecular determinants of the toxic damage and associated myocardial remodeling remain to be established. Furthermore, details on the different propensity of the left and right ventricle (LV and RV, respectively) to the cardiotoxicity development are unknown. Hence, the aim of the investigation was to study molecular changes associated with remodeling of the LV and RV in chronic anthracycline cardiotoxicity and post-treatment follow up. The cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg/week for 10 weeks) and animals were sacrificed either at the end of the treatment or after an additional 10 weeks. Daunorubicin induced severe and irreversible cardiotoxicity associated with LV dysfunction and typical morphological alterations, whereas the myocardium of the RV showed only mild changes. Both ventricles also showed different expression of ANP after daunorubicin treatment. Daunorubicin impaired the expression of several sarcomeric proteins in the LV, which was not the case of the RV. In particular, a significant drop was found in titin and thick filament proteins at both mRNA and protein level and this might be connected with persistent LV down-regulation of GATA-4. In addition, the LV was more affected by treatment-induced perturbations in calcium handling proteins. LV cardiomyocytes showed marked up-regulation of desmin after the treatment and vimentin was mainly induced in LV fibroblasts, whereas only weaker changes were observed in the RV. Remodeling of extracellular matrix was almost exclusively found in the LV with particular induction of collagen I and IV. Hence, the present study describes profound molecular remodeling of myocytes, non-myocyte cells and extracellular matrix in response to chronic anthracycline treatment with marked asymmetry between LV and RV.
Highlights
Anthracycline antibiotics (ANT, e.g., doxorubicin, epirubicin or daunorubicin) rank among the most effective anticancer drugs, but their clinical use has been hampered by the risk of cardiotoxicity
There was a tendency towards a raise of the left ventricular (LV) end-diastolic pressure at the end of the DAU treatment, it was markedly and significantly elevated in the post-treatment follow up (Fig. 1D) which further confirms the severity of the LV dysfunction at this stage
Significant induction of ANP gene expression was found in both ventricles after the DAU treatment, but it was apparently more distinct in the LV myocardium (Fig. 2A and Fig. 2B)
Summary
Anthracycline antibiotics (ANT, e.g., doxorubicin, epirubicin or daunorubicin) rank among the most effective anticancer drugs, but their clinical use has been hampered by the risk of cardiotoxicity. Several types of ANT cardiotoxicity have been recognized, the most important are chronic forms associated with dilated cardiomyopathy and heart failure [1,2]. They develop within the first year from ANT exposure (early onset form) or with a delay of several years (late onset form) and both are largely irreversible [2]. The chronic cardiotoxicity is common to all ANT derivatives introduced into the clinical practice and the severity of the toxic damage depends on the lifetime cumulative dose of the drug, significant inter-individual variability has been reported [2,3]. Different ANT derivatives have been demonstrated to induce practically indistinguishable histopathological hallmarks when administered in repeated cycles to patients as well as to different animal species, including dogs, rabbits or rodents [9]
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