1574P - Differential regulation of profibrotic genes responsible for cardiotoxicity after experimental anticancer treatments

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Transcriptomic analysis of the myocardial samples aimed to search genes responsible for myocardial fibrosis and development of heart failure induced by anticancer therapy under experimental setting. Domestic pigs (38 ± 3 kg) received 3 cycles of cytostatic treatment of human dose with either doxorubicin (DOX, n = 6) or liposomal encapsulation of doxorubicin-citrat complex (Myocet® MYO, n = 9), or epirubicin (EPI, n = 9) or physiologic saline (Controls, CO, n = 6). Left (LV) and right ventricular (RV) ejection fraction (EF) was assessed after the application of the last dose by cardiac magnetic resonance imaging. LV and RV myocardial fibrosis was quantified by picrosorius-red staining. mRNAs of myocardial samples from the LV and RV were isolated. The gene expression profile was analyzed by next generation sequencing (NGS) followed by post-hoc RT-PCR of selected genes. Five, 6 and 2 animals survived the treatment in DOX, MYO and EPI groups, respectively, thus EPI was excluded from the functional analysis. Both MYO and DOX resulted in decrease of LV EF (56.4 ± 5.6% vs 41.9 ± 13.5%, p < 0.05) and RV EF (42.1 ± 2.8% vs 28.9 ± 8.9%, p < 0.05) in MYO vs DOX, resp., with a trend towards less myocardial fibrosis in MYO-treated animals. The cardiac muscle contraction gene myozenin was significantly (p < 0.05) down-regulated in group DOX as compared to group MYO (0.12 ± 0.09 vs 1.13 ± 0.06 log fold changes /LFC/). EMILIN and SERPINH1 genes (both are involved in biosynthetic pathway of collagen and elastin) were significantly overexpressed in LV and RV samples of both DOX and MYO groups. Besides activations of tumor-repressors, both DOX and MYO treatments led to up-regulation of several proto-oncogenes, such as JUNB (LV: 1.68 ± 0.3 and 1.65 ± 0.23; RV:1.71 ± 0.13 and 1.98 ± 0.93 LFC, resp.) or BCL3 (LV: 2.97 ± 0.34 and 2.96 ± 0.79; RV: 6.34 ± 0.61 and 4.81 ± 1.01 LFC, resp.). Myocet® proved to be less cardiotoxic as compared with DOX, resulting in better cardiac function and less fibrosis. However, both cytostatic treatments led to overexpression of collagen-associated genes and proto-oncogenes, which might explain the development of myocardial fibrosis and secondary malignancies.